Glutamine Triggers Acetylation-Dependent Degradation of Glutamine Synthetase via the Thalidomide Receptor Cereblon
Open accessAbstract
Cereblon (CRBN), a substrate receptor for the cullin-RING ubiquitin ligase 4 (CRL4) complex, is a direct protein target for thalidomide teratogenicity and antitumor activity of immunomodulatory drugs (IMiDs). Here we report that glutamine synthetase (GS) is an endogenous substrate of CRL4(CRBN). Upon exposing cells to high glutamine concentration, GS is acetylated at lysines 11 and 14, yielding a degron that is necessary and sufficient for binding and ubiquitylation by CRL4(CRBN) and degradation by the proteasome. Binding of acetylated degron peptides to CRBN depends on an intact thalidomide-binding pocket but is not competitive with IMiDs. These findings reveal a feedback loop involving CRL4(CRBN) that adjusts GS protein levels in response to glutamine and uncover a new function for lysine acetylation.
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Claims the paper makes
9 of 17 cited sources checked · 7 supported · 0 flagged · accuracy not yet measured
- Premisecitation
ZNRF1 is expressed primarily in the nervous system.
“ZNFR1 is expressed primarily in the nervous system (Araki et al., 2001), suggesting that it is unlikely to play a ‘pan-organismal’ role.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Araki et al., 2001 source
- Premisecitation
GS is subject to feedback control by glutamine, which promotes its post-translational modification and degradation.
“It has been shown that GS is subject to feedback control by glutamine, which promotes its post-translational modification and degradation (Arad et al., 1976; Crook and Tomkins, 1978).”
Quote in the paperSubstantial claim1 of 2 sources checked- cites Arad et al., 1976 source
- cites Crook and Tomkins, 1978 source
The Abstract and Discussion report that extracellular glutamine regulates glutamine synthetase activity by changing its rate of degradation in hepatoma tissue-culture cells. The Discussion says the degradation mechanism is unknown: covalent modification is only a possibility, and the authors consider proteolytic cleavage more compatible with their data. The claim's assertion that glutamine promotes post-translational modification is therefore not established by this paper. (LLM, conf=0.90)
Experimental — accuracy not yet measured
- Interpretationcitation
ZNRF1 is unlikely to play a pan-organismal role in GS degradation.
“ZNFR1 is expressed primarily in the nervous system (Araki et al., 2001), suggesting that it is unlikely to play a ‘pan-organismal’ role.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Araki et al., 2001 source
- Findingown data
GS is an endogenous substrate of CRL4CRBN.
“Here we report that glutamine synthetase (GS) is an endogenous substrate of CRL4CRBN.”
- Also stated in: § GS is an endogenous substrate of CRL4CRBN · hedged
“Collectively, these results argue that GS is an endogenous ubiquitylation substrate of CRL4CRBN.”
Quote in the paperSubstantial claim - Also stated in: § GS is an endogenous substrate of CRL4CRBN · hedged
- Findingown data
Binding of acetylated GS degron peptides to CRBN is not competitive with IMiDs.
“Binding of acetylated degron peptides to CRBN depends on an intact thalidomide-binding pocket but is not competitive with IMiDs.”
- Also stated in: § The N-terminal extension of GS comprises an acetyllysine degron that binds the C-terminal domain of CRBN · plain
“pomalidomide did not block FlagCRBN binding to di-acetylated peptide, but promoted the interaction between FlagCRBN and peptide mono-acetylated at K11 or K14 (Figure 6H).”
Quote in the paperSubstantial claim - Also stated in: § The N-terminal extension of GS comprises an acetyllysine degron that binds the C-terminal domain of CRBN · plain
- Findingown data
Exposure of cells to high glutamine causes acetylation of GS at lysines 11 and 14.
“Upon exposing cells to high glutamine concentration, GS is acetylated at lysines 11 and 14, yielding a degron that is necessary and sufficient for binding and ubiquitylation by CRL4CRBN and degradation by the proteasome.”
- Also stated in: § Glutamine-dependent acetylation of lysines 11 and 14 by CBP/p300 regulates GS degradation · plain
“We conclude that GS can be acetylated on K11 and K14 in cells.”
Quote in the paperSubstantial claim - Also stated in: § Glutamine-dependent acetylation of lysines 11 and 14 by CBP/p300 regulates GS degradation · plain
- Findingown data
Binding of acetylated GS degron peptides to CRBN requires an intact thalidomide-binding pocket.
“Binding of acetylated degron peptides to CRBN depends on an intact thalidomide-binding pocket but is not competitive with IMiDs.”
Quote in the paperSubstantial claim - Findingown data
Glutamine-induced downregulation of GS is blocked by the proteasome inhibitor bortezomib or the NEDD8-activating enzyme inhibitor MLN4924.
“The glutamine-induced downregulation of GS in Hep3B cells was blocked by the addition of the proteasome inhibitor bortezomib or the NEDD8-activating enzyme inhibitor MLN4924 (Figure 2B)”
Quote in the paperSubstantial claim - Findingown data
Mass spectrometry identified K11 and K14 as independently acetylated residues on GS.
“Two lysine residues, K11 and K14, were found to be independently acetylated based on the conclusive mass spectra (Figure S5A and S5B, and Table S4).”
Quote in the paperSubstantial claim - Findingown data
A KxxK motif at lysines 11 and 14 of GS is highly conserved in chordates.
“We next investigated whether a KxxK motif (lysines 11 and 14) that is highly conserved in chordates (Figure S3) was required for GS binding to CRBN.”
Quote in the paperSubstantial claim - Findingown data
Antibodies against acetyl-lysine show that CRBN enriches for acetylated forms of GS.
“However, we have used antibodies against acetyl-lysine to show that CRBN enriches for acetylated forms of GS.”
Quote in the paperSubstantial claim - Findingown data
GS can be acetylated on K11 and K14 in cells.
“We conclude that GS can be acetylated on K11 and K14 in cells.”
Quote in the paperSubstantial claim - Findingown data
Production and testing of the N351R and H357Y FlagCRBN mutants confirmed the predicted effects on degron binding.
“Remarkably, production and testing of the indicated FlagCRBN mutants confirmed these predictions (Figures 6F – G), suggesting that the GS-peptide binding site overlaps or is adjacent to the IMiD pocket.”
Quote in the paperSubstantial claim- Rests on an assumption: The N351R and H357Y mutations affect degron binding specifically through the IMiD pocket and its electrostatic environment.
- Findingown data
The destabilizing effect of glutamine and HDACi is blunted by simultaneous treatment with C646 or garcinol.
“The destabilizing effect of glutamine and HDACi was blunted by simultaneous treatment with C646 or a distinct p300/CBP inhibitor, garcinol (Figures 5E and S6B).”
Quote in the paperSubstantial claim - Findingown data
IMiDs enhanced binding of monoacetylated GS peptides.
“In fact, IMiDs actually enhanced binding of monoacetylated GS peptides.”
Quote in the paperSubstantial claim - Findingown data
IMiDs did not compete out binding of the acetylated GS degron peptide to CRBN.
“However, IMiDs did not compete out binding of the acetylated GS degron peptide to CRBN.”
Quote in the paperSubstantial claim - Findingown data
Mutation of K11 and K14 of GS to alanine enhanced binding and ubiquitylation of GS by CRBN.
“Moreover, mutation of the critical lysines 11 and 14 of GS to alanine enhanced binding and ubiquitylation of GS by CRBN.”
Quote in the paperSubstantial claim - Findingown data
All activities of the N-terminal GS degron are blocked by RR substitutions.
“However, all of these activities of the N-terminal degron were blocked by the RR substitutions.”
Quote in the paperSubstantial claim - Findingown data
CRBN-dependent effects on GS downregulation are not due to changes in GS mRNA levels.
“For the Hep3B, myeloma, and lung cancer cell lines we confirmed that CRBN-dependent effects on GS downregulation were not due to changes in its mRNA level (Figure S2I–K).”
Quote in the paperSubstantial claim - Findingown data
No tryptic peptide with both K11 and K14 acetylated was detected.
“However, we were unable to detect a tryptic peptide in which both residues were acetylated (see legend of Figure S5 for a detailed discussion).”
Quote in the paperNot a substantial claim - Findingown data
A GS peptide acetylated at both K11 and K14, but not non-acetylated or mono-acetylated peptides, efficiently pulls down recombinant FlagCRBN.
“The peptide acetylated at both K11 and K14, but not non-acetylated or mono-acetylated peptides, efficiently pulled-down recombinant FlagCRBN (Figure 6E).”
Quote in the paperSubstantial claim- Rests on an assumption: The synthetic GS peptide spanning amino acids 5–22 recapitulates the N-terminal degron of full-length GS.
- Findingown data
The recombinant p300-HAT domain acetylates recombinant GS6xHis in vitro.
“Moreover, recombinant p300-HAT domain acetylated recombinant GS6xHis in vitro (Figure S4D).”
Quote in the paperSubstantial claim - Findingreasoning
Crbn−/− mice exhibit an increased serum glutamine to glutamate ratio.
“Crbn−/− mice exhibited an increased glutamine to glutamate ratio in serum (Figure 2G and table S3).”
Quote in the paperSubstantial claim- Rests on an assumption: The increased serum glutamine to glutamate ratio in Crbn−/− mice reflects elevated GS in peripheral tissues.
- Findingown data
Single alanine substitutions at either K11 or K14 result in significantly less binding and ubiquitylation than double AA mutations at both sites.
“Consistent with the peptide binding analysis, single substitutions at either K11 or K14 with alanine (A) resulted in significantly less binding and ubiquitylation, compared with double AA mutations at both K11 and K14 (Figure S6E, F).”
Quote in the paperSubstantial claim - Findingown data
Steady-state GS levels are elevated in CRBN-depleted cells.
“Consistent with a role for CRBN in GS degradation, the steady-state level of GS was elevated in CRBN-depleted cells (Figure S2G).”
Quote in the paperSubstantial claim - Findingown data
A modest glutamine-stimulated loss of GS remains in cell lines depleted of CRBN by shRNA or CRISPR/Cas9.
“Second, there remains a modest glutamine-stimulated loss of GS in cell lines depleted of CRBN by either shRNA or CRISPR/Cas9.”
Quote in the paperNot a substantial claim - Findingown data
Glutamine-induced downregulation of GS is blunted when CRBN is disrupted by CRISPR/Cas9 or depleted by shRNA.
“Most importantly, the glutamine-induced downregulation of GS in Hep3B cells was blunted upon disruption of CRBN loci by CRISPR/Cas9 (Figure 2C) or depletion of CRBN by shRNA knockdown (Figure S2D).”
Quote in the paperSubstantial claim - Findingown data
Histone deacetylase inhibitors enhance glutamine-induced downregulation of endogenous GS.
“If glutamine-stimulated acetylation of K11 and K14 on GS triggers its ubiquitylation and degradation, we reasoned that histone deacetylase inhibitors (HDACi) might enhance glutamine-induced downregulation of endogenous GS. Indeed, this was observed to be the case (Figure 5D; mRNA analysis in Figure S6A).”
Quote in the paperSubstantial claim - Findingown data
HDACi-induced degradation of endogenous GS is mediated by CRBN, as it is attenuated by genetic or chemical reduction of CRL4CRBN activity.
“HDACi-induced degradation of endogenous GS was mediated by CRBN because it was significantly attenuated by genetic (Figure 5F) or chemical (Figure S6C & D) reduction of CRL4CRBN activity.”
Quote in the paperSubstantial claim - Interpretationown data
A CRL4CRBN feedback loop adjusts GS protein levels in response to glutamine.
“These findings reveal a feedback loop involving CRL4CRBN that adjusts GS protein levels in response to glutamine and uncover a new function for lysine acetylation.”
- Also stated in: § CRL4CRBN directly controls the glutamine-induced degradation of GS · hedged
“Taken together, our data suggest that endogenous GS protein levels are negatively regulated by glutamine through a feedback loop involving CRL4CRBN.”
Quote in the paperSubstantial claim - Also stated in: § CRL4CRBN directly controls the glutamine-induced degradation of GS · hedged
- Interpretationown data
CRBN exhibits a strong preference for binding acetylated GS.
“We conclude that CRBN exhibits a strong preference for binding acetylated GS.”
Quote in the paperSubstantial claim - Interpretationreasoning
The acetylated GS peptide binds adjacent to the IMiD pocket by a novel mechanism.
“Our data suggest that the acetylated peptide binds adjacent to the IMiD pocket by a novel mechanism, the description of which awaits a crystal structure of the GS degron peptide bound to CRBN.”
Quote in the paperNot a substantial claim - Interpretationown data
The findings reveal a new function for lysine acetylation.
“These findings reveal a feedback loop involving CRL4CRBN that adjusts GS protein levels in response to glutamine and uncover a new function for lysine acetylation.”
Quote in the paperSubstantial claim - Interpretationown data
Modification of lysine residues in the N-terminal extension of GS is critical for its binding to and ubiquitylation by CRBN.
“Together, these findings suggest that modification of lysine(s) in the N-terminal extension of GS was critical for its binding to and ubiquitylation by CRBN.”
Quote in the paperSubstantial claim - Interpretationown data
This work establishes an unexpected molecular link between CRBN, acetylation, and metabolic control.
“Our work establishes an unexpected molecular link between CRBN, acetylation, and metabolic control.”
Quote in the paperSubstantial claim - Interpretationreasoning
Acetylation neutralizes positive charges on K11 and K14 that otherwise interfere with binding to CRBN.
“Together, these results suggest that acetylation neutralizes the positive charges on K11 and K14, which otherwise interfere with binding to CRBN.”
Quote in the paperSubstantial claim - Interpretationown data
Acetylation of GS on both lysine residues 11 and 14 contributes to CRBN binding, ubiquitylation, and degradation.
“These results indicate that acetylation of GS on both lysine residues 11 and 14 contributes to CRBN binding, ubiquitylation and degradation.”
Quote in the paperSubstantial claim
- May combine two claims. 23
- Classified as probably not a substantial claim. 9
May combine two claims.
PremisecitationCRBN acts as a substrate receptor for CRL4 and is the direct target mediating thalidomide teratogenicity and the antitumor effects of IMiDs.
“Cereblon (CRBN), a substrate receptor for the cullin–RING ubiquitin ligase 4 (CRL4) complex, is a direct protein target for thalidomide teratogenicity and antitumor activity of immunomodulatory drugs (IMiDs).”
Quote in the paperSubstantial claim1 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe tri-Trp pocket of CRBN shows 100% conservation in CRBN orthologs across animal and plant kingdoms.
“These residues form a small hydrophobic pocket (tri-Trp pocket), which shows 100% conservation in CRBN orthologs across animal and plant kingdoms (Chamberlain et al., 2014; Fischer et al., 2014) (Figure S7A).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites Chamberlain et al., 2014 source
- cites Fischer et al., 2014 source
The IMiD binding to CRBN section describes a hydrophobic pocket lined by three tryptophans and says its surface groove is highly conserved across CRBN orthologues. Extended Data Figure 1 lists animal orthologues for the conservation analysis, but the copy does not establish 100% conservation or extend that finding to plants. (LLM, conf=0.89)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationA prior study reported that GS degradation in Schwann cells is mediated by the ubiquitin ligase ZNRF1.
“We note that a prior study reported that GS degradation in Schwann cells is mediated by ubiquitin ligase ZNRF1 (Saitoh and Araki, 2010), but regulation by glutamine levels was not investigated.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Saitoh and Araki, 2010 source
May combine two claims.
Findingown dataFlagCRBN-W386E, FlagCRBN-W400E, and the double mutant FlagCRBN-Y384A/W386A fail to bind endogenous GS.
“FlagCRBN-W386E and FlagCRBN-W400E, and the double point mutant FlagCRBN-Y384A/W386A (FlagCRBN-YW/AA, which is defective in IMiD binding (Ito et al., 2010; Lopez-Girona et al., 2012)) failed to bind endogenous GS (Figure 6C).”
Quote in the paperSubstantial claim1 of 2 sources checked- Rests on an assumption: The CRBN point mutants used in binding assays do not disrupt overall CRBN folding.
Classified as probably not a substantial claim.
PremisecitationThe CRBN CTD contains the IMiD binding pocket formed by Trp380, Trp386, and Trp400, with Phe402 at its base.
“The CTD harbors the IMiD binding pocket formed by Trp380, Trp386 and Trp400, with a phenylalanine residue at the base (Phe402) (Chamberlain et al., 2014; Fischer et al., 2014).”
Quote in the paperSubstantial claim1 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationGS is a homodecamer composed of two pentameric rings.
“In mammals, GS is a homodecamer composed of two pentameric rings (Krajewski et al., 2008).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Krajewski et al., 2008 source
May combine two claims.
Findingown dataMutating all Ser, Thr, and Tyr residues in the N-terminal 24 amino acids of GS to Ala retained some CRBN binding, suggesting phosphorylation does not play a major role.
“Notably, all mutants retained some binding to CRBN (Figure S4A), suggesting that phosphorylation does not play a major role.”
Quote in the paperSubstantial claimMay combine two claims.
FindingcitationIn CRBN-KO 293FT cells, GSFlag acetylation is significantly enhanced by coexpression with p300HA or by treatment with histone deacetylase inhibitors.
“Furthermore, in 293FT CRBN knockout cells (CRBN-KO 293FT) (Lu et al., 2014), GSFlag acetylation was significantly enhanced upon coexpression with p300HA or treatment with histone deacetylase inhibitors (HDACi) (Figure 5A).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Lu et al., 2014
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Findingown dataGlutamine downregulates GS protein levels in Hep3B cells and in multiple lung, breast, and glioblastoma cancer cell lines.
“we observed that glutamine downregulated GS protein levels upon addition to glutamine-starved Hep3B cells (Figure 2A) as well as to multiple lung, breast, and glioblastoma cancer cell lines (Figure S1E).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataWild-type GSMyc, but not the corresponding AA or RR mutants, yields a robust anti-acetyllysine signal.
“Wild-type GSMyc, but not the corresponding AA or RR mutants, yielded a robust signal (Figure 5B and Figure S4E).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe N-terminal 24 amino acids of GS are required for its constitutive interaction with CRBN and for its degradation in glutamine-supplemented medium.
“we generated a series of deletion mutants and found that the N-terminal 24–amino acids were required for its constitutive interaction with CRBN (Figures 3A and 3B) and degradation (Figure 3C) in glutamine-supplemented medium.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
FindingreasoningIt has been difficult to identify by mass spectrometry acetylation of K11 and K14 on GS bound to CRBN, probably because of low sequence coverage for endogenous CRBN-bound GS.
“Although we provide strong evidence to support these conclusions, we note that it has been difficult to identify by mass spectrometry acetylation of lysines 11 and 14 on GS bound to CRBN. This is probably due to low sequence coverage obtained for endogenous GS bound to CRBN.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe GS pentamer interface contains electrostatic interactions involving K11 and K14, and the Lys11 ε-amino group forms a salt bridge with aspartate 174 in the neighboring subunit.
“The pentamer interface contains a network of electrostatic interactions involving both K11 and K14. In particular the ε-amino group of Lysine 11 is normally engaged in a salt bridge with aspartate 174 in the neighboring subunit (Figure S7B, C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataDouble alanine substitutions at K11 and K14 enhance GS binding to CRBN, ubiquitylation, and degradation, whereas double arginine substitutions diminish or do not affect these activities.
“We analyzed double arginine substitutions (RR; keeps the positive charges) and double alanine substitutions (AA; neutralizes the positive charges) at K11 and K14 and found that the binding to CRBN, ubiquitylation, and degradation of GS were enhanced by the AA mutations but diminished or unaffected by the RR mutations (Figures 3D–F).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataGlutamine does not cause complete GS degradation; the reduction ranges from 50% to 80% depending on the cell line.
“First, glutamine does not induce complete degradation of GS; depending upon the cell line, the reduction ranged from 50–80%.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataPomalidomide does not block FlagCRBN binding to the di-acetylated GS peptide, but promotes the interaction between FlagCRBN and peptide mono-acetylated at K11 or K14.
“pomalidomide did not block FlagCRBN binding to di-acetylated peptide, but promoted the interaction between FlagCRBN and peptide mono-acetylated at K11 or K14 (Figure 6H).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe carboxy-terminal domain of CRBN is necessary and sufficient for binding endogenous GS.
“We next mapped the GS-binding region on CRBN by deletion analysis and found that the carboxy-terminal domain (CTD) was necessary and sufficient for binding endogenous GS (Figures 6A and B).”
Quote in the paperSubstantial claimMay combine two claims.
FindingcitationGlutamine markedly stimulates GSFlag acetylation, and this effect is largely blocked by RR mutations and by the CBP/p300 inhibitor C646.
“Aetylation of GSFlag was markedly stimulated by glutamine but this effect was largely blocked by the RR mutations and the CBP/p300 inhibitor C646 (Bowers et al., 2010) (Figure 5C).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Bowers et al., 2010 source
May combine two claims.
Findingown dataGS is elevated in kidney, skeletal muscle, and lung of Crbn−/− mice, but not in brain and liver.
“GS was elevated in the kidney, skeletal muscle and lung of Crbn−/− mice, but not in the brain and liver (data not shown).”
Quote in the paperSubstantial claim- The authors state this as an assumption: The mouse starvation and re-feeding protocol reproduces glutamine starvation and re-feeding conditions used in cultured cells.
May combine two claims.
Findingown dataThe N-terminal region of GS (amino acids 1-25) is sufficient to confer binding to and ubiquitylation by CRBN, as well as degradation.
“The N-terminal region of GS was sufficient to confer binding to and ubiquitylation by CRBN, as well as degradation (Figures 4B–D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataGSMyc co-immunoprecipitates with both p300HA and CBPHA.
“Consistent with GS being a potential CBP/p300 substrate, GSMyc co-immunoprecipitated with both p300HA and CBPHA (Figure S4C).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown dataThe N-terminal segment of GS is absent from bacterial GS enzymes but is conserved throughout the chordate lineage.
“Intriguingly, this N-terminal segment is absent from bacterial GS enzymes but is conserved in GS throughout the chordate lineage (Figure S3).”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataThe acetylated K11/K14 degron is necessary and sufficient for GS degradation by the proteasome.
“yielding a degron that is necessary and sufficient for binding and ubiquitylation by CRL4CRBN and degradation by the proteasome”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe acetylated K11/K14 degron is necessary and sufficient for GS binding and ubiquitylation by CRL4CRBN.
“yielding a degron that is necessary and sufficient for binding and ubiquitylation by CRL4CRBN and degradation by the proteasome”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningHigh glutamine concentrations cause a conformational change in GS that disrupts the ionic interface and exposes the N-terminal extension so that K11 and K14 can be bound by p300/CBP and acetylated.
“We propose that high glutamine concentrations cause a conformational change in GS that disrupts this ionic interface and exposes the N-terminal extension such that lysines 11 and 14 can be bound by p300/CBP and acetylated.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataEnhanced binding of the H357Y mutant to the mono-acetylated K11 peptide, but not the mono-acetylated K14 peptide, implicates electrostatics in recognition of acetylated GS peptides.
“Enhanced binding of the H357Y mutant to the mono-acetylated K11 peptide but not the mono-acetylated K14 peptide (Figure S6G) further implicates electrostatics as contributing to recognition of the acetylated GS peptides.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Premisenone givenThe molecular basis for glutamine regulation of GS remains elusive.
“However, the molecular basis for this regulation remains elusive.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningZNRF1 may contribute to the residual GS degradation observed in CRBN-depleted cells.
“ZNFR1 may contribute to residual GS degradation that we observed in CRBN-depleted cells.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
InterpretationreasoningAcetylation-dependent ubiquitylation by CRL4CRBN may be a general feature of metabolic regulation.
“We suggest that acetylation-dependent ubiquitylation by CRL4CRBN may be a general feature of metabolic regulation.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataCRBN promotes rapid glutamine-dependent downregulation of GS through a post-transcriptional mechanism that requires Nedd8 conjugation and proteasome activity.
“Nevertheless, it is clear that CRBN promotes rapid, glutamine-dependent downregulation of GS by a post-transcriptional mechanism that requires Nedd8 conjugation and proteasome activity.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataA model in which high glutamine causes p300/CBP to acetylate GS at K11 and K14, creating a degron that binds CRBN; the bound acetylated GS is ubiquitylated and degraded by the proteasome.
“After exposure of cells to high glutamine, p300/CPB proteins acetylate GS at lysines 11 and 14 to create a degron that binds CRBN. Acetylated GS bound to CRBN is ubiquitylated and subsequently is degraded by the proteasome.”
Quote in the paperSubstantial claim
The authors state this as an assumption.
The mouse starvation and re-feeding protocol reproduces glutamine starvation and re-feeding conditions used in cultured cells.
“to mimic glutamine starvation/re-feeding in cultured cells”
The paper relies on this without support.
The synthetic GS peptide spanning amino acids 5–22 recapitulates the N-terminal degron of full-length GS.
“we generated biotinylated synthetic peptides (amino acids 5–22 of GS) that were unmodified, mono-acetylated on either K11 or K14, or di-acetylated (Figure 6D).”
The paper relies on this without support.
The CRBN point mutants used in binding assays do not disrupt overall CRBN folding.
“FlagCRBN-W386E and FlagCRBN-W400E, and the double point mutant FlagCRBN-Y384A/W386A (FlagCRBN-YW/AA, which is defective in IMiD binding (Ito et al., 2010; Lopez-Girona et al., 2012)) failed to bind endogenous GS (Figure 6C).”
The paper relies on this without support.
The increased serum glutamine to glutamate ratio in Crbn−/− mice reflects elevated GS in peripheral tissues.
“Consistent with the accumulation of GS in these tissues, Crbn−/− mice exhibited an increased glutamine to glutamate ratio in serum (Figure 2G and table S3).”
The paper relies on this without support.
The N351R and H357Y mutations affect degron binding specifically through the IMiD pocket and its electrostatic environment.
“We reasoned that the substitution of N351R might block degron binding by occluding the IMiD pocket whereas H357Y might enhance degron binding by decreasing the cationic charge surrounding the IMiD pocket.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
This is a conserved mode of regulation for GS, as CRBN and glutamine can induce degradation of GS in HCC, myeloma, breast cancer, and lung cancer.
“This is a conserved mode of regulation for GS, as CRBN and glutamine can induce degradation of GS in HCC, myeloma, breast cancer, and lung cancer [62].”
From Acetylation: a new target for protein degradation in cancer (2025) · cites this paper as [62]
The Results section (“CRL4CRBN directly controls the glutamine-induced degradation of GS,” Figures 2A–C and S1E–S2F) reports glutamine-induced GS loss in Hep3B, myeloma, breast, and lung cancer cell lines. CRBN depletion blunted that loss in Hep3B, myeloma, and lung cells, but CRBN dependence was not directly shown in breast cells; there, the paper reports inhibition by MLN4924, which acts on Cullin-RING ligases more broadly. Page numbers are unavailable in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredGS is acetylated at K11 and K14 under high glutamine conditions by p300 to allow recognition by E3 ligase CRBN and thus GS degradation.
“GS is acetylated at K11 and K14 under high glutamine conditions by p300 to allow for recognition by E3 ligase cereblon (CRBN) and thus GS degradation (Figure 2C) [62].”
From Acetylation: a new target for protein degradation in cancer (2025) · cites this paper as [62]
PZ has no significant effect on expression of the CRBN native substrate glutamine synthetase and neosubstrates CK1α, IKZF1, and IKZF3.
“This is further supported by the observations that PZ could selectively induce Bcl-xl but not Bcl-2 poly-ubiquitination and had no significant effect on the expression of the CRBN native substrate, glutamine synthetase (GS)36, and its neosubstrates recruited by thalidomide and its analogues including CK1α37, IKZF1, and IKZF3 (ref. 38) (Supplementary Fig. 1 f, g).”
From Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity (2020) · cites this paper as [36]
The transcription factors Ikaros, Aiolos, and MEIS2 are localized to the nucleus.
“The subcellular localizations of these factors differ: the transcription factors Ikaros, Aiolos, and MEIS2 are localized to the nucleus, whereas GSPT1, CK1α, and glutamine synthetase reside in the cytoplasm.”
From Genome-wide screening reveals a role for subcellular localization of CRBN in the anti-myeloma activity of pomalidomide (2020) · cites this paper as [24]
Over a dozen proteins, including Ikaros, Aiolos, GSPT1, CK1α, glutamine synthetase, MEIS2, KCNMA1/SLO1, CLC1, and AMPKα, have been identified as substrates for CRBN.
“To date, over a dozen proteins including Ikaros, Aiolos, GSPT1, CK1α, glutamine synthetase, MEIS2, KCNMA1/SLO1, CLC1, and AMPKα have been identified as substrates for CRBN3,11–16,24–28.”
From Genome-wide screening reveals a role for subcellular localization of CRBN in the anti-myeloma activity of pomalidomide (2020) · cites this paper as [24]
GSPT1, CK1α, and glutamine synthetase reside in the cytoplasm.
“The subcellular localizations of these factors differ: the transcription factors Ikaros, Aiolos, and MEIS2 are localized to the nucleus, whereas GSPT1, CK1α, and glutamine synthetase reside in the cytoplasm.”
From Genome-wide screening reveals a role for subcellular localization of CRBN in the anti-myeloma activity of pomalidomide (2020) · cites this paper as [24]
Aryl sulfonamides have produced modest response rates as monotherapy in clinical trials involving patients with advanced-stage solid tumours.
“which to date have produced modest response rates as monotherapy in clinical trials involving patients with advanced-stage solid tumours173–176.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [175]
The first class of additional molecular glue degraders comprises aryl sulfonamides, including indisulam, tasisulam, E7820 and chloroquinoxaline.
“The first class comprises aryl sulfonamides, including indisulam, tasisulam, E7820 and chloroquinoxaline”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [175]
CRBN controls glutamine metabolism and acetylation is needed for degradation of some substrates of CRBN.
“That study indicated that CRBN controls glutamine metabolism and acetylation is needed for degradation of some substrates of CRBN [42].”
From Cereblon and its downstream substrates as molecular targets of immunomodulatory drugs (2016) · cites this paper as [42]
Glutamine induces acetylation-dependent breakdown of glutamine synthetase via CRBN.
“More recently, it was reported that glutamine induces acetylation-dependent breakdown of glutamine synthetase via CRBN.”
From Cereblon and its downstream substrates as molecular targets of immunomodulatory drugs (2016) · cites this paper as [42]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
CBP/p300 is misstated as CPB/p300
MinorThe discussion text names the acetyltransferases as "p300/CPB proteins," but elsewhere the paper consistently refers to "CBP/p300". This is an internal naming inconsistency for the same enzyme pair.
“After exposure of cells to high glutamine, p300/CPB proteins acetylate GS at lysines 11 and 14 to create a degron that binds CRBN.”
“Consistent with GS being a potential CBP/p300 substrate, GSMyc co-immunoprecipitated with both p300HA and CBPHA (Figure S4C).”
ZNFR1 is misspelled as ZNFR1
MinorThe paper refers to the ubiquitin ligase as ZNRF1 earlier, but later the same protein is written twice as "ZNFR1". This is an internal inconsistency in the protein name, though not a numeric error.
“We note that a prior study reported that GS degradation in Schwann cells is mediated by ubiquitin ligase ZNRF1 (Saitoh and Araki, 2010), but regulation by glutamine levels was not investigated. ZNFR1 is expressed primarily in the nervous system (Araki et al., 2001), suggesting that it is unlikely to play a ‘pan-organismal’ role. ZNFR1 may contribute to”
“We note that a prior study reported that GS degradation in Schwann cells is mediated by ubiquitin ligase ZNRF1 (Saitoh and Araki, 2010), but regulation by glutamine levels was not investigated.”
Two different spellings are used for the same protein name
MinorThe discussion section uses both "ZNRF1" and "ZNFR1" for the ubiquitin ligase linked to GS degradation. Those names differ by letter order, so the manuscript is internally inconsistent about the protein identity.
“We note that a prior study reported that GS degradation in Schwann cells is mediated by ubiquitin ligase ZNRF1 (Saitoh and Araki, 2010), but regulation by glutamine levels was not investigated.”
“ZNFR1 is expressed primarily in the nervous system (Araki et al., 2001), suggesting that it is unlikely to play a ‘pan-organismal’ role.”
Cites
Lysine acetylation targets protein complexes and co-regulates major cellular functions
Choudhary, C., Kumar, C., Gnad, F., Nielsen, M. L., Rehman, M., Walther, T. C., Olsen, J. V., & Mann, M. (2009) · Science · doi:10.1126/science.1175371 · Cited by 4,040 · cited 1× · see citing works
“Recent proteomic analyses suggest that it regulates many metabolic enzymes (Choudhary et al., 2009; Wang et al., 2010; Zhao et al., 2010).”
Identification of a Primary Target of Thalidomide Teratogenicity
Ito, T., Ando, H., Suzuki, T., Ogura, T., Hotta, K., Imamura, Y., Yamaguchi, Y., & Handa, H. (2010) · Science · doi:10.1126/science.1177319 · Cited by 2,136 · cited 4× · see citing works
“FlagCRBN-W386E and FlagCRBNW400E, and the double point mutant FlagCRBN-Y384A/W386A (FlagCRBN-YW/AA, which is defective in IMiD binding (Ito et al., 2010; Lopez-Girona et al., 2012)) failed to”
InfluentialSelf-citationAn inhibitor of NEDD8-activating enzyme as a new approach to treat cancer
Soucy, T. A., Smith, P. G., Milhollen, M. A., Berger, A. J., Gavin, J. M., Adhikari, S., Brownell, J. E., Burke, K. E., Cardin, D. P., Critchley, S., et al. (2009) · Nature · doi:10.1038/nature07884 · Cited by 1,990 · cited 2× · see citing works
“addition of the proteasome inhibitor bortezomib or the NEDD8-activating enzyme inhibitor MLN4924 (Figure 2B), which inactivates Cullin-RING E3 ubiquitin ligase activity (Soucy et al., 2009).”
Regulation of cellular metabolism by protein lysine acetylation
Zhao, S., Xu, W., Jiang, W., Yu, W., Lin, Y., Zhang, T., Yao, J., Zhou, L., Zeng, Y., Li, H., et al. (2010) · Science · doi:10.1126/science.1179689 · Cited by 1,910 · cited 3× · see citing works
“Recent proteomic analyses suggest that it regulates many metabolic enzymes (Choudhary et al., 2009; Wang et al., 2010; Zhao et al., 2010).”
Lenalidomide Causes Selective Degradation of IKZF1 and IKZF3 in Multiple Myeloma Cells
Krönke, J., Udeshi, N. D., Narla, A., Grauman, P., Hurst, S. N., McConkey, M., Svinkina, T., Heckl, D., Comer, E., Li, X., et al. (2014) · Science · doi:10.1126/science.1244851 · Cited by 1,879 · cited 10× · see citing works
“Recent studies have revealed that binding of IMiDs to CRBN promotes recruitment of neosubstrates, including Ikaros (IKZF1), Aiolos (IKZF3) (Kronke et al., 2014; Lu et al., 2014) and casein kinase 1A1 (CK1α) (Kronke et al., 2015) to CRL4CRBN, leading to their increased ubiquitylation and proteasome-dependent degradatio…”
InfluentialBidirectional Transport of Amino Acids Regulates mTOR and Autophagy
Nicklin, P., Bergman, P., Zhang, B., Triantafellow, E., Wang, H., Nyfeler, B., Yang, H., Hild, M., Kung, C., Wilson, C., et al. (2009) · Cell · doi:10.1016/j.cell.2008.11.044 · Cited by 1,798 · cited 3× · see citing works
“Moreover, glutamine has a critical role in regulating mTOR signaling, translation, and autophagy to coordinate cell growth and proliferation (Nicklin et al., 2009).”
InfluentialStructure and ligand of a histone acetyltransferase bromodomain
Dhalluin, C., Carlson, J. E., Zeng, L., He, C., Aggarwal, A. K., Zhou, M.-M., & Zhou, M.-M. (1999) · Nature · doi:10.1038/20974 · Cited by 1,732 · cited 2× · see citing works
“aromatic pocket binds thalidomide, lenalidomide, and pomalidomide, and is reminiscent of pockets found in proteins containing bromodomains (Dhalluin et al., 1999), plant homeodomain (PHD) fingers (Wysocka et al.”
The Myeloma Drug Lenalidomide Promotes the Cereblon-Dependent Destruction of Ikaros Proteins
Lu, G., Middleton, R. E., Sun, H., Naniong, M., Ott, C. J., Mitsiades, C. S., Wong, K.-K., Bradner, J. E., & Kaelin, W. G. (2014) · Science · doi:10.1126/science.1244917 · Cited by 1,583 · cited 12× · see citing works
“Recent studies have revealed that binding of IMiDs to CRBN promotes recruitment of neosubstrates, including Ikaros (IKZF1), Aiolos (IKZF3) (Kronke et al., 2014; Lu et al., 2014) and casein kinase 1A1 (CK1α) (Kronke et al., 2015) to CRL4CRBN, leading to their increased ubiquitylation and proteasome-dependent degradatio…”
InfluentialTaverna, S. D., Li, H., Ruthenburg, A. J., Allis, C. D., & Patel, D. J. (2007) · Nature Structural & Molecular Biology · doi:10.1038/nsmb1338 · Cited by 1,419 · cited 2× · see citing works
“malignant brain tumor (MBT) repeats, all of which have been implicated in binding to acetylated or methylated lysine (Taverna et al., 2007).”
The growing landscape of lysine acetylation links metabolism and cell signalling
Choudhary, C., Weinert, B. T., Nishida, Y., Verdin, E., & Mann, M. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3841 · Cited by 1,324 · cited 1× · see citing works
“It has been thought that lysine acetylation controls protein– protein interactions that regulate protein activity via acetyl-lysine-binding domains (Choudhary et al., 2014; Mujtaba et al., 2007).”
Glutamine and cancer: cell biology, physiology, and clinical opportunities
Hensley, C. T., Wasti, A. T., & DeBerardinis, R. J. (2013) · Journal of Clinical Investigation · doi:10.1172/jci69600 · Cited by 1,262 · cited 1× · see citing works
“Skeletal muscle and lung GS plays a significant role in regulating the concentration of plasma glutamine (Hensley et al., 2013).”
A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling
Wysocka, J., Swigut, T., Xiao, H., Milne, T. A., Kwon, S. Y., Landry, J., Kauer, M., Tackett, A. J., Chait, B. T., Badenhorst, P. W., et al. (2006) · Nature · doi:10.1038/nature04815 · Cited by 1,186 · cited 2× · see citing works
“, 1999), plant homeodomain (PHD) fingers (Wysocka et al., 2006), chromodomains, Tudor domains, and”
THALIDOMIDE AND CONGENITAL ABNORMALITIES
Mcbride, W. G. (1961) · The Lancet · doi:10.1016/s0140-6736(61)90927-8 · Cited by 1,141 · see citing works
Structure of the DDB1–CRBN E3 ubiquitin ligase in complex with thalidomide
Fischer, E. S., Böhm, K., Lydeard, J. R., Yang, H., Stadler, M. B., Cavadini, S., Nagel, J., Serluca, F., Acker, V., Lingaraju, G. M., et al. (2014) · Nature · doi:10.1038/nature13527 · Cited by 1,141 · cited 11× · see citing works
“which shows 100% conservation in CRBN orthologs across animal and plant kingdoms (Chamberlain et al., 2014; Fischer et al., 2014) (Figure S7A).”
InfluentialAcetylation of Metabolic Enzymes Coordinates Carbon Source Utilization and Metabolic Flux
Wang, Q., Zhang, Y., Yang, C., Xiong, H., Lin, Y., Yao, J., Li, H., Xie, L., Zhao, W., Yao, Y., et al. (2010) · Science · doi:10.1126/science.1179687 · Cited by 1,008 · cited 3× · see citing works
“Recent proteomic analyses suggest that it regulates many metabolic enzymes (Choudhary et al., 2009; Wang et al., 2010; Zhao et al., 2010).”
Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS
Krönke, J., Fink, E. C., Hollenbach, P. W., MacBeth, K. J., Hurst, S. N., Udeshi, N. D., Chamberlain, P. P., Mani, D. R., Man, H. W., Gandhi, A. K., et al. (2015) · Nature · doi:10.1038/nature14610 · Cited by 863 · cited 9× · see citing works
“Recent studies have revealed that binding of IMiDs to CRBN promotes recruitment of neosubstrates, including Ikaros (IKZF1), Aiolos (IKZF3) (Kronke et al., 2014; Lu et al., 2014) and casein kinase 1A1 (CK1α) (Kronke et al., 2015) to CRL4CRBN, leading to their increased ubiquitylation and proteasome-dependent degradatio…”
BackgroundInfluentialWysocka, J., Swigut, T., Milne, T. A., Dou, Y., Zhang, X., Burlingame, A. L., Roeder, R. G., Brivanlou, A. H., & Allis, C. D. (2005) · Cell · doi:10.1016/j.cell.2005.03.036 · Cited by 820 · cited 2× · see citing works
“Peptide pull-down assay The assay was performed as described (Wysocka et al., 2005).”
Lopez-Girona, A., Mendy, D., Ito, T., Miller, K., Gandhi, A. K., Kang, J., Karasawa, S., Carmel, G., Jackson, P., Abbasian, M., et al. (2012) · Leukemia · doi:10.1038/leu.2012.119 · Cited by 814 · cited 3× · see citing works
“Subsequently, CRBN was implicated as the target that accounts for the therapeutic activity of thalidomide and the related ‘‘immunomodulatory’’ (IMiD) compounds lenalidomide and pomalidomide in multiple myeloma (Lopez-Girona et al., 2012; Zhu et al., 2011).”
BackgroundSelf-citationWeinert, B. T., Scholz, C. W., Wagner, S., Iešmantavičius, V., Su, D., Daniel, J. A., & Choudhary, C. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.07.024 · Cited by 757 · cited 2× · see citing works
“…because proteomic studies uncovered modification of K14 on human, mouse and rat GS (Chen et al., 2012; Lundby et al., 2012; Svinkina et al., 2015; Weinert et al., 2013), and more generally revealed that reversible lysine acetylation plays an important role in regulating metabolic enzymes (Wang…”
Molecular architecture and assembly of the DDB1–CUL4A ubiquitin ligase machinery
Angers, S., Li, T., Yi, X., MacCoss, M. J., Moon, R. T., & Zheng, N. (2006) · Nature · doi:10.1038/nature05175 · Cited by 674 · cited 2× · see citing works
“Cereblon (CRBN) is a putative substrate receptor for a cullin–RING ubiquitin ligase 4 (CRL4) complex (Angers et al., 2006).”
Bowers, E. M., Yan, G., Mukherjee, C., Orry, A., Wang, L., Holbert, M. A., Crump, N. T., Hazzalin, C. A., Liszczak, G., Yuan, H., et al. (2010) · Chemistry & Biology · doi:10.1016/j.chembiol.2010.03.006 · Cited by 666 · cited 4× · see citing works
“Aetylation of GSFlag was markedly stimulated by glutamine but this effect was largely blocked by the RR mutations and the CBP/p300 inhibitor C646 (Bowers et al., 2010) (Figure 5C).”
InfluentialCereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide
Zhu, Y. X., Braggio, E., Shi, C.-X., Bruins, L. A., Schmidt, J. E., Van Wier, S., Chang, X.-B., Bjorklund, C. C., Fonseca, R., Bergsagel, P. L., et al. (2011) · Blood · doi:10.1182/blood-2011-05-356063 · Cited by 607 · cited 2× · see citing works
“Subsequently, CRBN was implicated as the target that accounts for the therapeutic activity of thalidomide and the related ‘‘immunomodulatory’’ (IMiD) compounds lenalidomide and pomalidomide in multiple myeloma (Lopez-Girona et al., 2012; Zhu et al., 2011).”
Lv, L., Dong, L., Zhao, D., Lin, R., Chu, Y., Zhang, H., Zha, Z., Liu, Y., Li, Z., Xu, Y., et al. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.04.025 · Cited by 605 · cited 1× · see citing works
“Recent studies suggest that lysine acetylation can regulate the steady-state levels of metabolic enzymes by promoting their degradation through the ubiquitin-proteasome system or chaperone-mediated autophagy (Jiang et al., 2011; Lv et al., 2011).”
MDM2–HDAC1-mediated deacetylation of p53 is required for its degradation
Ito, A., Kawaguchi, Y., Lai, C., Kovacs, J. J., Higashimoto, Y., Appella, E., & Yao, T. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf616 · Cited by 570 · cited 2× · see citing works
“In some cases, lysine acetylation has been shown to compete with other post-translational modifications (e.g. ubiquitylation or SUMOylation), thereby controlling protein stability or transcriptional activity (Gronroos et al., 2002; Ito et al., 2002; Van Nguyen et al., 2012).”
BackgroundTardito, S., Oudin, A., Ahmed, S. U., Fack, F., Keunen, O., Zheng, L., Miletic, H., Sakariassen, P. Ø., Weinstock, A., Wagner, A., et al. (2015) · Nature Cell Biology · doi:10.1038/ncb3272 · Cited by 557 · cited 2× · see citing works
“linked to human diseases, including congenital glutamine deficiency, Alzheimer’s disease, and cancers (Bott et al., 2015; Christa et al., 1994; Gunnersen and Haley, 1992; Haberle et al., 2005; Kung et al., 2011; Tardito et al., 2015).”
Lundby, A., Lage, K., Weinert, B. T., Bekker‐Jensen, D. B., Secher, A., Skovgaard, T., Kelstrup, C. D., Dmytriyev, A., Choudhary, C., Lundby, C., et al. (2012) · Cell Reports · doi:10.1016/j.celrep.2012.07.006 · Cited by 544 · cited 2× · see citing works
“…CRBN. Acetylation was of particular interest, because proteomic studies uncovered modification of K14 on human, mouse and rat GS (Chen et al., 2012; Lundby et al., 2012; Svinkina et al., 2015; Weinert et al., 2013), and more generally revealed that reversible lysine acetylation plays an important…”
Chamberlain, P. P., Lopez-Girona, A., Miller, K., Carmel, G., Pagarigan, B., Chie-Leon, B., Rychak, E., Corral, L. G., Ren, Y. J., Wang, M., et al. (2014) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2874 · Cited by 531 · cited 3× · see citing works
“which shows 100% conservation in CRBN orthologs across animal and plant kingdoms (Chamberlain et al., 2014; Fischer et al., 2014) (Figure S7A).”
Self-citationStructure and acetyl-lysine recognition of the bromodomain
Mujtaba, S., Zeng, L., & Zhou, M.-M. (2007) · Oncogene · doi:10.1038/sj.onc.1210618 · Cited by 419 · cited 2× · see citing works
“It has been thought that lysine acetylation controls protein– protein interactions that regulate protein activity via acetyl-lysine-binding domains (Choudhary et al., 2014; Mujtaba et al., 2007).”
BackgroundTHALIDOMIDE AND CONGENITAL ABNORMALITIES
Lenz, W., Pfeiffer, R. A., Kosenow, W., & Hayman, D. J. (1962) · The Lancet · doi:10.1016/s0140-6736(62)92665-x · Cited by 418 · cited 1× · see citing works
“CRBN has achieved notoriety as the target that accounts for the teratogenic effects of thalidomide (Ito et al., 2010), which caused over 10,000 birth defects in humans before it was withdrawn from the market in 1962 (Lenz et al., 1962; Mcbride, 1961).”
BackgroundJiang, W., Wang, S., Xiao, M., Lin, Y., Zhou, L., Lei, Q., Xiong, Y., Guan, K., & Zhao, S. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.04.028 · Cited by 415 · cited 1× · see citing works
“Recent studies suggest that lysine acetylation can regulate the steady-state levels of metabolic enzymes by promoting their degradation through the ubiquitin-proteasome system or chaperone-mediated autophagy (Jiang et al., 2011; Lv et al., 2011).”
Control of Smad7 Stability by Competition between Acetylation and Ubiquitination
Gronroos, E. C., Hellman, U., Heldin, C., & Ericsson, J. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00639-1 · Cited by 383 · cited 2× · see citing works
“In some cases, lysine acetylation has been shown to compete with other post-translational modifications (e.g. ubiquitylation or SUMOylation), thereby controlling protein stability or transcriptional activity (Gronroos et al., 2002; Ito et al., 2002; Van Nguyen et al., 2012).”
THALIDOMIDE AND CONGENITAL ABNORMALITIES
Burley, D. M., & Lenz, W. (1962) · The Lancet · doi:10.1016/s0140-6736(62)91217-5 · Cited by 325 · cited 1× · see citing works
“, 2010), which caused over 10,000 birth defects in humans before it was withdrawn from the market in 1962 (Lenz et al., 1962; Mcbride, 1961).”
BackgroundFBXO11 targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas
Duan, S., C̆ermák, L., Pagan, J. K., Rossi, M., Martinengo, C., di Celle, P. F., Chapuy, B., Shipp, M. A., Chiarle, R., & Pagano, M. (2011) · Nature · doi:10.1038/nature10688 · Cited by 295 · cited 2× · see citing works
“In vitro ubiquitylation assay The assays were performed as described (Duan et al., 2012; Kleiger et al., 2009).”
Kung, H.-N., Marks, J. R., & Chi, J.-T. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1002229 · Cited by 277 · cited 2× · see citing works
“linked to human diseases, including congenital glutamine deficiency, Alzheimer’s disease, and cancers (Bott et al., 2015; Christa et al., 1994; Gunnersen and Haley, 1992; Haberle et al., 2005; Kung et al., 2011; Tardito et al., 2015).”
Oncogenic Myc Induces Expression of Glutamine Synthetase through Promoter Demethylation
Bott, A. J., Peng, I., Fan, Y., Faubert, B., Zhao, L. H., Li, J., Neidler, S., Sun, Y., Jaber, N. L., Krokowski, D., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.09.025 · Cited by 259 · cited 2× · see citing works
“linked to human diseases, including congenital glutamine deficiency, Alzheimer’s disease, and cancers (Bott et al., 2015; Christa et al., 1994; Gunnersen and Haley, 1992; Haberle et al., 2005; Kung et al., 2011; Tardito et al., 2015).”
A mutation in a novel ATP-dependent Lon protease gene in a kindred with mild mental retardation
Higgins, J. J., Pucilowska, J., Lombardi, R. Q., & Rooney, J. P. (2004) · Neurology · doi:10.1212/01.wnl.0000146196.01316.a2 · Cited by 250 · cited 1× · see citing works
“Human CRBN was discovered as a gene that when mutated results in mild mental retardation (Higgins et al., 2004).”
Congenital Glutamine Deficiency with Glutamine Synthetase Mutations
Häberle, J., Görg, B., Rutsch, F., Schmidt, E., Toutain, A., Benoist, J., Gélot, A., Suc, A., Höhne, W. E., Schliess, F., et al. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa050456 · Cited by 214 · cited 2× · see citing works
“linked to human diseases, including congenital glutamine deficiency, Alzheimer’s disease, and cancers (Bott et al., 2015; Christa et al., 1994; Gunnersen and Haley, 1992; Haberle et al., 2005; Kung et al., 2011; Tardito et al., 2015).”
Chen, Y., Zhao, W., Yang, J. S., Cheng, Z., Luo, H., Lu, Z., Tan, M., Gu, W. J., & Zhao, Y. (2012) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m112.019547 · Cited by 202 · cited 2× · see citing works
“Acetylation was of particular interest, because proteomic studies uncovered modification of K14 on human, mouse and rat GS (Chen et al., 2012; Lundby et al., 2012; Svinkina et al., 2015; Weinert et al., 2013), and more generally revealed that reversible lysine acetylation plays an important role in regulating metaboli…”
Kleiger, G., Saha, A., Lewis, S. M., Kuhlman, B. A., & Deshaies, R. J. (2009) · Cell · doi:10.1016/j.cell.2009.10.030 · Cited by 194 · cited 2× · see citing works
“In vitro ubiquitylation assay The assays were performed as described (Duan et al., 2012; Kleiger et al., 2009).”
Self-citationSvinkina, T., Gu, H., Silva, J. C., Mertins, P., Qiao, J., Fereshetian, S., Jaffe, J. D., Kuhn, E. W., Udeshi, N. D., & Carr, S. A. (2015) · Molecular & Cellular Proteomics · doi:10.1074/mcp.o114.047555 · Cited by 179 · cited 2× · see citing works
“…of particular interest, because proteomic studies uncovered modification of K14 on human, mouse and rat GS (Chen et al., 2012; Lundby et al., 2012; Svinkina et al., 2015; Weinert et al., 2013), and more generally revealed that reversible lysine acetylation plays an important role in regulating…”
The Story of Glutamine Synthetase Regulation
Stadtman, E. R. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.r100055200 · Cited by 147 · cited 2× · see citing works
“In keeping with its central role in carbon and nitrogen metabolism, prokaryotic GS is allosterically regulated by multiple end products of glutamine metabolism working in concert with cycles of reversible adenylylation/deadenylylation (Krajewski et al., 2008; Stadtman, 2001).”
Glutamine metabolism: Role in acid‐base balance*
Taylor, L. E., & Curthoys, N. P. (2004) · Biochemistry and Molecular Biology Education · doi:10.1002/bmb.2004.494032050388 · Cited by 136 · cited 1× · see citing works
“For example in liver it detoxifies ammonia, in brain it protects neurons against excitotoxicity by converting glutamate into glutamine, and in kidney it contributes to pH regulation (Taylor and Curthoys, 2004).”
Krajewski, W. W., Collins, R., Holmberg-Schiavone, L., Jones, T. A., Karlberg, T., & Mowbray, S. L. (2008) · Journal of Molecular Biology · doi:10.1016/j.jmb.2007.10.029 · Cited by 135 · cited 3× · see citing works
“In mammals, GS is a homodecamer composed of two pentameric rings (Krajewski et al., 2008).”
Transcriptional Coactivator Protein p300
Thompson, P. R., Kurooka, H., Nakatani, Y., & Cole, P. A. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m104736200 · Cited by 132 · see citing works
The inhibition by glutamine of glutamyl transferase formation in cultures of human cells
DeMars, R. (1958) · Biochimica et Biophysica Acta · doi:10.1016/0006-3002(58)90367-6 · Cited by 126 · cited 2× · see citing works
“Discussion Almost sixty years ago, it was reported that mammalian GS is inactivated by extracellular glutamine (Demars, 1958; Paul and Fottrell, 1963).”
Nguyen, T. V., Angkasekwinai, P., Dou, H., Lin, F.-M., Lu, L., Cheng, J., Chin, Y. E., Dong, C., & Yeh, E. T. H. (2012) · Molecular Cell · doi:10.1016/j.molcel.2011.12.026 · Cited by 126 · cited 4× · see citing works
“[PubMed: 20167786] Zhu YX, Braggio E, Shi CX, Bruins LA, Schmidt JE, Van Wier S, Chang XB, Bjorklund CC, Fonseca R, Bergsagel PL, et al. Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide.”
InfluentialSelf-citationJo, S., Lee, K., Song, S., Jung, Y., & Park, C. (2005) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03344.x · Cited by 120 · cited 2× · see citing works
“To date, only four putative targets of CRBN have been identified: large conductance Ca2+-activated K+ channels (Jo et al., 2005), voltage-gated chloride channel (Hohberger and Enz, 2009), the developmental regulator MEIS2 (Fischer et al.”
Self-citationOverexpression of glutamine synthetase in human primary liver cancer
Christa, L., Simon, M., Flinois, J.-P., Gebhardt, R., Bréchot, C., & Lasserre, C. (1994) · Gastroenterology · doi:10.1016/0016-5085(94)90024-8 · Cited by 102 · cited 2× · see citing works
“linked to human diseases, including congenital glutamine deficiency, Alzheimer’s disease, and cancers (Bott et al., 2015; Christa et al., 1994; Gunnersen and Haley, 1992; Haberle et al., 2005; Kung et al., 2011; Tardito et al., 2015).”
Functional modulation of AMP-activated protein kinase by cereblon
Lee, K. M., Jo, S., Kim, H., Lee, J., & Park, C. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2011.01.005 · Cited by 92 · cited 8× · see citing works
“However, the mechanism by which CRBN recognizes AMPK or its other natural substrates remains unknown.”
InfluentialSelf-citationGunnersen, D., & Haley, B. E. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.24.11949 · Cited by 85 · cited 2× · see citing works
“linked to human diseases, including congenital glutamine deficiency, Alzheimer’s disease, and cancers (Bott et al., 2015; Christa et al., 1994; Gunnersen and Haley, 1992; Haberle et al., 2005; Kung et al., 2011; Tardito et al., 2015).”
Lee, K. M., Yang, S.-J., Kim, Y. D., Choi, Y. D., Nam, J. H., Choi, C. S., Choi, H.-S., & Park, C.-S. (2013) · Diabetes · doi:10.2337/db12-1030 · Cited by 77 · cited 9× · see citing works
“However, the mechanism by which CRBN recognizes AMPK or its other natural substrates remains unknown.”
InfluentialSelf-citationIdentification of Genes Induced in Peripheral Nerve after Injury
Araki, T., Nagarajan, R., & Milbrandt, J. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m104271200 · Cited by 76 · cited 1× · see citing works
“H H M I A uthor M anuscript H H M I A uthor M anuscript H H M I A uthor M anuscript ZNFR1 is expressed primarily in the nervous system (Araki et al., 2001), suggesting that it is unlikely to play a ‘pan-organismal’ role.”
BackgroundProteasomal degradation of glutamine synthetase regulates schwann cell differentiation
Saitoh, F., & Araki, T. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.3591-09.2010 · Cited by 70 · cited 1× · see citing works
“We note that a prior study reported that GS degradation in Schwann cells is mediated by ubiquitin ligase ZNRF1 (Saitoh and Araki, 2010), but regulation by glutamine levels was not investigated.”
Lee, J. E., Sweredoski, M. J., Graham, R. L. J., Kolawa, N. J., Smith, G. T., Hess, S. Y., & Deshaies, R. J. (2010) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m110.006460 · Cited by 60 · cited 8× · see citing works
“However, the mechanism by which CRBN recognizes AMPK or its other natural substrates remains unknown.”
InfluentialSelf-citationArad, G., Freikopf, A., & Kulka, R. G. (1976) · Cell · doi:10.1016/0092-8674(76)90190-2 · Cited by 54 · cited 6× · see citing works
“Subsequent work done prior to the discovery of the ubiquitin system suggested that glutamine stimulates the modification and degradation of GS enzyme through an unknown mechanism (Arad et al., 1976; Crook and Tomkins, 1978).”
InfluentialCereblon is expressed in the retina and binds to voltage‐gated chloride channels
Hohberger, B., & Enz, R. (2009) · FEBS Letters · doi:10.1016/j.febslet.2009.01.018 · Cited by 51 · cited 2× · see citing works
“…four putative targets of CRBN have been identified: large conductance Ca2+-activated K+ channels (Jo et al., 2005), voltage-gated chloride channel (Hohberger and Enz, 2009), the developmental regulator MEIS2 (Fischer et al., 2014), and adenosine monophosphateactivated protein kinase (AMPK) (Lee…”
Mechanism of d-glutamyltransferase repression in mammalian cells
Paul, J., & FOTTRELL, P. F. (1963) · Biochimica et Biophysica Acta (BBA) - Specialized Section on Enzymological Subjects · doi:10.1016/0926-6569(63)90247-5 · Cited by 47 · cited 1× · see citing works
“Almost 60 years ago, it was reported that mammalian GS is inactivated by extracellular glutamine (Demars, 1958; Paul and Fottrell, 1963).”
Effect of glutamine on the degradation of glutamine synthetase in hepatoma tissue-culture cells
Crook, R. B., & Tomkins, G. M. (1978) · Biochemical Journal · doi:10.1042/bj1760047 · Cited by 29 · cited 7× · see citing works
“Subsequent work done prior to the discovery of the ubiquitin system suggested that glutamine stimulates the modification and degradation of GS enzyme through an unknown mechanism (Arad et al., 1976; Crook and Tomkins, 1978).”
InfluentialLee, K. M., Yang, S., Choi, J., & Park, C. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.523423 · Cited by 29 · cited 8× · see citing works
“However, the mechanism by which CRBN recognizes AMPK or its other natural substrates remains unknown.”
InfluentialSelf-citationMechanism of d-glutamyltransferase repression in mammalian cells
Paul, J., & FOTTRELL, P. F. (1963) · Biochimica et Biophysica Acta · doi:10.1016/0006-3002(63)91836-5 · Cited by 15 · see citing works
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The hallmarks of cancer metabolism: still emerging
Pavlova, N. N., Zhu, J., & Thompson, C. B. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.01.007 · Cited by 1,418 · see citing works
Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead
Bondeson, D. P., Smith, B. E., Burslem, G. M., Buhimschi, A. D., Hines, J., Jaime-Figueroa, S., Wang, J., Hamman, B. D., Ishchenko, A., & Crews, C. M. (2018) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.09.010 · Cited by 923 · see citing works
“…E3 ubiquitin ligase commonly used in PROTAC design is Cereblon (CRBN), which is the substrate adapter for the Cullin 4a E3 ligase complex whose endogenous substrates have not been fully characterized, but likely include MEIS2 and glutamine synthetase (Fischer et al., 2014; Nguyen et al., 2016).”
BackgroundGlutamine Metabolism in Cancer: Understanding the Heterogeneity
Cluntun, A. A., Lukey, M. J., Cerione, R. A., & Locasale, J. W. (2017) · Trends in Cancer · doi:10.1016/j.trecan.2017.01.005 · Cited by 796 · see citing works
Cancer cell metabolism: the essential role of the nonessential amino acid, glutamine
Zhang, J., Pavlova, N. N., & Thompson, C. B. (2017) · The EMBO Journal · doi:10.15252/embj.201696151 · Cited by 651 · see citing works
“…acute myeloid leukemia (AML) and metastatic liver cancer are characterized by significant elevation of the enzymes for glutathione biosynthesis, including GCL and GS (Pei et al , 2013; Nguyen et al , 2016a), suggesting that these tumors might be sensitive to inhibitors of glutathione biosynthesis.”
Ubiquitylation at the crossroads of development and disease
Rapé, M. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.83 · Cited by 608 · see citing works
Donovan, K. A., An, J., Nowak, R. P., Yuan, J. C., Fink, E. C., Berry, B. C., Ebert, B. L., & Fischer, E. S. (2018) · eLife · doi:10.7554/elife.38430 · Cited by 509 · see citing works
PROTACs: An Emerging Therapeutic Modality in Precision Medicine
Nalawansha, D. A., & Crews, C. M. (2020) · Cell chemical biology · doi:10.1016/j.chembiol.2020.07.020 · Cited by 514 · see citing works
Development of targeted protein degradation therapeutics
Chamberlain, P. P., & Hamann, L. G. (2019) · Nature Chemical Biology · doi:10.1038/s41589-019-0362-y · Cited by 489 · see citing works
As Extracellular Glutamine Levels Decline, Asparagine Becomes an Essential Amino Acid
Pavlova, N. N., Hui, S., Ghergurovich, J. M., Fan, J., Intlekofer, A. M., White, R. M., Rabinowitz, J. D., Thompson, C. B., & Zhang, J. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2017.12.006 · Cited by 341 · see citing works
“Notably, GLUL protein was previously shown to be upregulated in glutamine-depleted cells in a post-transcriptional manner (Nguyen et al., 2016).”
He, Y., Zhang, X., Chang, J., Kim, H.-N., Zhang, P., Wang, Y., Khan, S., Liu, X., Zhang, X., Lv, D., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-15838-0 · Cited by 280 · see citing works
Cullin-RING Ubiquitin Ligase Regulatory Circuits: A Quarter Century Beyond the F-Box Hypothesis
Harper, J. W., & Schulman, B. A. (2021) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-090120-013613 · Cited by 252 · see citing works
A Role for p53 in the Adaptation to Glutamine Starvation through the Expression of SLC1A3
Tajan, M., Hock, A. K., Blagih, J., Robertson, N. A., Labuschagne, C. F., Kruiswijk, F., Humpton, T. J., Adams, P. D., & Vousden, K. H. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.07.005 · Cited by 230 · see citing works
“GS catalyzes the condensation of glutamate and ammonia into glutamine, and wild-type p53 cells showed a strong stabilization of GS in response to glutamine starvation (Figure S1B), as previously reported (Nguyen et al., 2016).”
ResultDysregulation of glutaminase and glutamine synthetase in cancer
Matés, J. M., Campos-Sandoval, J. A., Santos-Jiménez, J. D. L., & Márquez, J. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.09.011 · Cited by 197 · see citing works
The E3 ligase adapter cereblon targets the C-terminal cyclic imide degron
Ichikawa, S., Flaxman, H. A., Xu, W., Vallavoju, N., Lloyd, H. C., Wang, B., Shen, D., Pratt, M. R., & Woo, C. M. (2022) · Nature · doi:10.1038/s41586-022-05333-5 · Cited by 195 · see citing works
pSILAC mass spectrometry reveals ZFP91 as IMiD-dependent substrate of the CRL4CRBN ubiquitin ligase
An, J., Ponthier, C. M., Sack, R., Seebacher, J., Stadler, M. B., Donovan, K. A., & Fischer, E. S. (2017) · Nature Communications · doi:10.1038/ncomms15398 · Cited by 176 · see citing works
Nitrogen Metabolism in Cancer and Immunity
Kurmi, K., & Haigis, M. C. (2020) · Trends in Cell Biology · doi:10.1016/j.tcb.2020.02.005 · Cited by 161 · see citing works
“GS expression is not only induced during glutamine starvation [47] but also by oncogenic c-MYC in cancer [18].”
BackgroundYamamoto, J., Ito, T., Yamaguchi, Y., & Handa, H. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00116k · Cited by 164 · see citing works
Self-citationUncovering post-translational modification-associated protein–protein interactions
Wang, S., Osgood, A. O., & Chatterjee, A. (2022) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2022.102352 · Cited by 153 · see citing works
Composition and Regulation of the Cellular Repertoire of SCF Ubiquitin Ligases
Reitsma, J. M., Liu, X., Reichermeier, K. M., Moradian, A., Sweredoski, M. J., Hess, S. Y., & Deshaies, R. J. (2017) · Cell · doi:10.1016/j.cell.2017.10.016 · Cited by 144 · see citing works
“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript Generation of stable cell lines—Lentivirus were generated as described (Nguyen et al., 2016).”
Self-citationAn E3 ligase guide to the galaxy of small-molecule-induced protein degradation
Jevtić, P., Haakonsen, D. L., & Rapé, M. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.04.002 · Cited by 144 · see citing works
Expanding the arsenal of E3 ubiquitin ligases for proximity-induced protein degradation
Kannt, A., & Đikić, I. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.04.007 · Cited by 149 · see citing works
Collins, I., Wang, H., Caldwell, J., & Chopra, R. (2017) · Biochemical Journal · doi:10.1042/bcj20160762 · Cited by 135 · see citing works
Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide
Jan, M., Sperling, A. S., & Ebert, B. L. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-021-00479-z · Cited by 137 · see citing works
The Pleiotropic Effects of Glutamine Metabolism in Cancer
Bott, A. J., Maimouni, S., & Zong, W. (2019) · Cancers · doi:10.3390/cancers11060770 · Cited by 111 · see citing works
Blocking an N-terminal acetylation–dependent protein interaction inhibits an E3 ligase
Scott, D. C., Hammill, J. T., Min, J., Rhee, D. Y., Connelly, M., Sviderskiy, V. O., Bhasin, D., Chen, Y., Ong, S. S., Chai, S. C., et al. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2386 · Cited by 108 · see citing works
“Although specific interactions involving acetylated protein N-termini are only beginning to emerge, some potentially therapeutically relevant targets include ubiquitin E3 ligases, cytoskeletal assemblies, epigenetic regulators, and protein trafficking and quality control pathways 1–7,11 ,12, 43”
Target protein localization and its impact on PROTAC-mediated degradation
Simpson, L. M., Glennie, L., Brewer, A., Zhao, J., Crooks, J., Shpiro, N., & Sapkota, G. P. (2022) · Cell chemical biology · doi:10.1016/j.chembiol.2022.08.004 · Cited by 100 · see citing works
p97/VCP promotes degradation of CRBN substrate glutamine synthetase and neosubstrates
Nguyen, T. V., Li, J., Lu, C.-C. (., Mamrosh, J. L., Lu, G., Cathers, B. E., & Deshaies, R. J. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1700949114 · Cited by 85 · see citing works
“However, the molecular events that take place at each step of the Significance We have recently reported that glutamine synthetase (GS) is negatively regulated by glutamine through a feedback loop involving the E3 ubiquitin ligase CRL4CRBN.”
BackgroundInfluentialSelf-citationGlial Glutamine Homeostasis in Health and Disease
Andersen, J. V., & Schousboe, A. (2022) · Neurochemical Research · doi:10.1007/s11064-022-03771-1 · Cited by 88 · see citing works
A Brighter Side to Thalidomide: Its Potential Use in Immunological Disorders
Millrine, D., & Kishimoto, T. (2017) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2017.02.006 · Cited by 87 · see citing works
Yamanaka, S., Horiuchi, Y., Matsuoka, S., Kido, K., Nishino, K., Maeno, M., Shibata, N., Kosako, H., & Sawasaki, T. (2022) · Nature Communications · doi:10.1038/s41467-021-27818-z · Cited by 86 · see citing works
Glutamine Synthetase as a Therapeutic Target for Cancer Treatment
Kim, G. W., Lee, D. H., Jeon, Y. H., Yoo, J. H., Kim, S. Y., Lee, S. W., Cho, H. Y., & Kwon, S. H. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22041701 · Cited by 86 · see citing works
Self-citationCereblon and its downstream substrates as molecular targets of immunomodulatory drugs
Ito, T., & Handa, H. (2016) · International Journal of Hematology · doi:10.1007/s12185-016-2073-4 · Cited by 84 · see citing works
Self-citationHumanized cereblon mice revealed two distinct therapeutic pathways of immunomodulatory drugs
Gemechu, Y., Millrine, D., Hashimoto, S., Prakash, J., Sanchenkova, K., Metwally, H., Parajuli, G., Kang, S., & Kishimoto, T. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1814446115 · Cited by 81 · see citing works
“Recently, the acetylated form of glutamine synthetase (13), MEIS2 (14), Rabex-5 (15), and uridine (16) were proved to be substrate proteins that bind to CRBN under physiological condition.”
BackgroundZhou, Q., Lin, W., Wang, C., Sun, F., Ju, S., Chen, Q., Wang, Y., Chen, Y., Li, H., Wang, L., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-30559-2 · Cited by 80 · see citing works
Molecular mechanisms of cereblon-based drugs
Asatsuma‐Okumura, T., Ito, T., & Handa, H. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.06.004 · Cited by 77 · see citing works
Self-citationGlutamine Synthetase: Localization Dictates Outcome
Castegna, A., & Menga, A. (2018) · Genes · doi:10.3390/genes9020108 · Cited by 73 · see citing works
“Furthermore, there are many other factors regulating glutamine metabolism, such as the activity of c-Jun [85], retinoblastoma protein (pRb) [86,87], peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)/estrogen-related receptor-alpha (ERRα) [88], GS acetylation levels [89], and others [90,91].”
BackgroundThe emerging role for Cullin 4 family of E3 ligases in tumorigenesis
Cheng, J., Guo, J., North, B. J., Tao, K., Zhou, P., & Wei, W. (2018) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2018.11.007 · Cited by 69 · see citing works
Heim, C., Pliatsika, D., Mousavizadeh, F., Bär, K., Alvarez, B. H., Giannis, A., & Hartmann, M. D. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b00454 · Cited by 72 · see citing works
Negi, A., & Voisin‐Chiret, A. S. (2022) · ChemBioChem · doi:10.1002/cbic.202100689 · Cited by 68 · see citing works
Ubiquitin-specific proximity labeling for the identification of E3 ligase substrates
Huang, H., Lumpkin, R. J., Tsai, R. W., Su, S., Zhao, X., Xiong, Y., Chen, J., Mageed, N., Donovan, K. A., Fischer, E. S., et al. (2024) · Nature Chemical Biology · doi:10.1038/s41589-024-01590-9 · Cited by 64 · see citing works
“Furthermore, HIF1A 36,37 and GLUL 38 were among the top hits within the proximal ubiquitome of VHL and CRBN, respectively, suggesting that E-STUB has the potential for physiological substrate discovery (Extended Data Fig.”
Shi, Q., & Chen, L. (2017) · Journal of Immunology Research · doi:10.1155/2017/9130608 · Cited by 62 · see citing works
“This process functions as a negative feedback mechanism under high glutamine concentrations [17, 18].”
BackgroundMinireview on Glutamine Synthetase Deficiency, an Ultra-Rare Inborn Error of Amino Acid Biosynthesis
Spodenkiewicz, M., Díez‐Fernández, C., Rüfenacht, V., Gemperle-Britschgi, C., & Häberle, J. (2016) · Biology · doi:10.3390/biology5040040 · Cited by 62 · see citing works
Tsai, P.-Y., Lee, M.-S., Jadhav, U., Naqvi, I., Madha, S., Adler, A., Mistry, M., Naumenko, S., Lewis, C. A., Hitchcock, D. S., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2003014118 · Cited by 64 · see citing works
SIRT1 deacetylated and stabilized XRCC1 to promote chemoresistance in lung cancer
Yousafzai, N. A., Zhou, Q.-Y., Xu, W., Shi, Q.-Q., Xu, J.-Y., Feng, L.-F., Chen, H.-J., Shin, V., Jin, H.-C., & Wang, X. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1592-3 · Cited by 55 · see citing works
Ito, T., Yamaguchi, Y., & Handa, H. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.04.012 · Cited by 60 · see citing works
Self-citationTargeting mTORC2/HDAC3 Inhibits Stemness of Liver Cancer Cells Against Glutamine Starvation
Zhang, H., Chen, P., Yan, H., Fu, G., Luo, F., Zhang, J., Zhao, S., Zhai, B., Yu, J., Chen, L., et al. (2022) · Advanced Science · doi:10.1002/advs.202103887 · Cited by 54 · see citing works
Targeting cereblon in hematologic malignancies
Fuchs, O. (2023) · Blood Reviews · doi:10.1016/j.blre.2022.100994 · Cited by 55 · see citing works
Ubiquitination Links DNA Damage and Repair Signaling to Cancer Metabolism
Koo, S.-Y., Park, E., Noh, H.-J., Jo, S.-M., Ko, B.-K., Shin, H.-J., & Lee, C. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24098441 · Cited by 56 · see citing works
“Moreover, glutamine synthetase (GS) catalyzes the conversion of glutamate and ammonia into glutamine, and Cullin-RING ubiquitin ligase 4 (CRL4) facilitates the ubiquitination and proteasomal degradation of GS [69].”
BackgroundCereblon in health and disease
Kim, H. K., Ko, T. H., Nyamaa, B., Lee, S. R., Kim, N., Ko, K. S., Rhee, B. D., Park, C., Nilius, B., & Han, J. (2016) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-016-1854-1 · Cited by 55 · see citing works
Self-citationThe molecular mechanism of thalidomide analogs in hematologic malignancies
Lindner, S., & Krönke, J. (2016) · Journal of Molecular Medicine · doi:10.1007/s00109-016-1450-z · Cited by 50 · see citing works
Degrons: defining the rules of protein degradation
Zhang, Z., Mena, E. L., Timms, R. T., Koren, I., & Elledge, S. J. (2025) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-025-00870-z · Cited by 57 · see citing works
“CRBN recognizes cyclic imide degrons, which mimic thalidomide 36,218 , but also binds an acetyl-degron through an adjacent pocket 219 ; HERC2 recognizes CCT4 and NCOA4 through distinct domains 170,220 .”
Yang, J., Huang, M. J., Zhou, L., He, X., Jiang, X., Zhang, Y., & Xu, G. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.002246 · Cited by 47 · see citing works
“This E3 ligase, CRL4CRBN, can mediate the ubiquitination and degradation of endogenous substrates, such as the homeobox protein MEIS2 (32), calcium-activated potassium channel subunit -1 (34), glutamine synthetase (35, 36), adenosine monophosphate–activated protein kinase subunit 1 (37), chloride channel protein 1 (38…”
BackgroundGlutamine metabolism in cancer therapy
Nguyen, T.-L., & Durán, R. V. (2018) · Cancer Drug Resistance · doi:10.20517/cdr.2018.08 · Cited by 52 · see citing works
“Moreover, GS is inactivated by extracellular glutamine because the presence of glutamine induces GS acetylation by p300/CBP protein, facilitating its ubiquitination and proteasomal degradation([79-81]).”
BackgroundSelf-citationGlutamine synthetase is necessary for sarcoma adaptation to glutamine deprivation and tumor growth
Issaq, S. H., Mendoza, A., Fox, S. D., & Helman, L. J. (2019) · Oncogenesis · doi:10.1038/s41389-019-0129-z · Cited by 49 · see citing works
Cereblon Maintains Synaptic and Cognitive Function by Regulating BK Channel
Choi, T.-Y., Lee, S., Kim, Y.-J., Bae, J. R., Lee, K. M., Jo, Y., Kim, S., Lee, A.-R., Choi, S., Choi, L., et al. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.2081-17.2018 · Cited by 42 · see citing works
“…1A1 (Krönke et al., 2015), IKZF1 and 3 (Krönke et al., 2014; Lu et al., 2014; Zhu et al., 2014), MEIS2 (Fischer et al., 2014), glutamine synthetase (Nguyen et al., 2016, 2017), CLC channels (Hohberger and Enz, 2009; Ronstedt et al., 2015), and BK channels, which are large-conductance…”
BackgroundSelf-citationUSP15 antagonizes CRL4 CRBN -mediated ubiquitylation of glutamine synthetase and neosubstrates
Nguyen, T. V. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2111391118 · Cited by 49 · see citing works
“based on the in vitro ubiquitylation assays, which were described in two recent studies (46, 47).”
BackgroundMethodInfluentialSelf-citationTyagi, A., Kaushal, K., Chandrasekaran, A. P., Sarodaya, N., Das, S., Park, C., Hong, S., Kim, K.-S., & Ramakrishna, S. (2022) · Theranostics · doi:10.7150/thno.72826 · Cited by 44 · see citing works
“To confirm the specificity of MAST1 ubiquitination and to avoid non-specific binding of polyubiquitin molecules to MAST1 protein, we washed the protein-bound beads with lysis buffer containing 300 mM NaCl for the experiments represented in Figure 4J and Figure S6A as previously described [29].”
MethodSelf-citationSmall-Molecule Approaches to Targeted Protein Degradation
Faust, T. B., Donovan, K. A., Yue, H., Chamberlain, P. P., & Fischer, E. S. (2020) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-051420-114114 · Cited by 45 · see citing works
Nguyen, T.-L., Nokin, M., Terés, S., Tomé, M., Bodineau, C., Galmar, O., Pasquet, J., Rousseau, B., van Liempd, S., Falcón‐Pérez, J. M., et al. (2020) · Molecular Oncology · doi:10.1002/1878-0261.12877 · Cited by 41 · see citing works
Self-citationDevelopment of Photolenalidomide for Cellular Target Identification
Lin, Z., Amako, Y., Kabir, F., Flaxman, H. A., Budnik, B., & Woo, C. M. (2022) · Journal of the American Chemical Society · doi:10.1021/jacs.1c11920 · Cited by 43 · see citing works
Design and Evaluation of a Cyclobutane Diazirine Alkyne Tag for Photoaffinity Labeling in Cells
West, A. V., Amako, Y., & Woo, C. M. (2022) · Journal of the American Chemical Society · doi:10.1021/jacs.2c08257 · Cited by 43 · see citing works
Disordered region of cereblon is required for efficient degradation by proteolysis-targeting chimera
Kim, K., Lee, D.-H., Park, S., Jo, S.-H., Ku, B., Park, S. G., Park, B. C., Jeon, Y. U., Ahn, S., Kang, C. H., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-56177-5 · Cited by 36 · see citing works
Reprogramming endothelial cells to empower cancer immunotherapy
Cleveland, A. H., & Fan, Y. (2023) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2023.11.002 · Cited by 43 · see citing works
Crbn modulates calcium influx by regulating Orai1 during efferocytosis
Moon, H., Min, C., Kim, G., Kim, D., Kim, K., Lee, S.-A., Moon, B., Yang, S., Lee, J., Yang, S., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19272-0 · Cited by 41 · see citing works
Self-citationTateno, S., Iida, M., Fujii, S., Suwa, T., Katayama, M., Tokuyama, H., Yamamoto, J., Ito, T., Sakamoto, S., Handa, H., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-61027-w · Cited by 36 · see citing works
Self-citationGlutaminase inhibition in multiple myeloma induces apoptosisviaMYC degradation
Effenberger, M., Bommert, K. S., Kunz, V., Kruk, J., Leich, E., Rudelius, M., Bargou, R. C., & Bommert, K. (2017) · Oncotarget · doi:10.18632/oncotarget.20691 · Cited by 36 · see citing works
“Interestingly the glutamine synthetase itself is under conditions of high glutamine levels targeted for degradation by the thalidomide receptor cereblon [31].”
BackgroundSubstrate and Functional Diversity of Protein Lysine Post-translational Modifications
Hao, B., Chen, K., Zhai, L., Liu, M., Liu, B., & Tan, M. (2024) · Genomics Proteomics & Bioinformatics · doi:10.1093/gpbjnl/qzae019 · Cited by 39 · see citing works
Krasavin, M., Adamchik, M., Bubyrev, A. I., Heim, C., Maiwald, S. A., Zhukovsky, D., Zhmurov, P. A., Bunev, A. S., & Hartmann, M. D. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.114990 · Cited by 36 · see citing works
Lai, Y., Li, J., Li, X., & Zou, C. (2017) · Journal of Cell Science · doi:10.1242/jcs.206904 · Cited by 34 · see citing works
“It demonstrates a third pattern of acetyldegron that p300/CBP-mediated acetylation of a tandem KxxK motif leads to glutamine synthetase ubiquitylation and proteasomal degradation (Van Nguyen et al., 2016).”
BackgroundChiu, M., Taurino, G., Bianchi, M. G., Ottaviani, L., Andreoli, R., Ciociola, T., Lagrasta, C. A. M., Tardito, S., & Bussolati, O. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19041099 · Cited by 31 · see citing works
Metabolic plasticity allows cancer cells to thrive under nutrient starvation
Palm, W. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2102057118 · Cited by 30 · see citing works
Targeting the E3 ubiquitin ligases DCAF15 and cereblon for cancer therapy
Nguyen, K. M., & Busino, L. (2020) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2020.03.007 · Cited by 28 · see citing works
Chiu, M., Taurino, G., Dander, E., Bardelli, D., Fallati, A., Andreoli, R., Bianchi, M. G., Carubbi, C., Pozzi, G., Galuppo, L., et al. (2021) · Blood Advances · doi:10.1182/bloodadvances.2020004041 · Cited by 30 · see citing works
“The proliferative rescue is associated with increased GS protein levels, likely achieved by decreased ubiquitin-dependent degradation, 39 transcription of the coding gene GLUL .”
Molecular Mechanisms of Cereblon-Interacting Small Molecules in Multiple Myeloma Therapy
Costacurta, M., He, J., Thompson, P. E., & Shortt, J. (2021) · Journal of Personalized Medicine · doi:10.3390/jpm11111185 · Cited by 28 · see citing works
“In the presence of high intracellular levels of glutamine, p300/CBP mediates acetylation of GS at lysine 11 and 14 [97].”
BackgroundKusch, K., Uecker, M., Liepold, T., Möbius, W., Hoffmann, C., Neumann, H., Werner, H. B., & Jahn, O. (2017) · Proteomes · doi:10.3390/proteomes5010003 · Cited by 27 · see citing works
Zhu, S., Gu, H., Peng, C. Y., Xia, F., Cao, H., & Cui, H. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.849625 · Cited by 29 · see citing works
The application of ubiquitin ligases in the PROTAC drug design
Chen, Y., & Jin, J. (2020) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gmaa053 · Cited by 28 · see citing works
Selective degradation-inducing probes for studying cereblon (CRBN) biology
Powell, C. E., Du, G., Bushman, J. W., He, Z., Zhang, T., Fischer, E. S., & Gray, N. S. (2021) · RSC Medicinal Chemistry · doi:10.1039/d0md00382d · Cited by 27 · see citing works
Cullin 4-DCAF Proteins in Tumorigenesis
Zhou, Z., Song, X., Wavelet, C. M., & Wan, Y. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-981-15-1025-0_15 · Cited by 27 · see citing works
Ubiquitin-dependent proteasomal degradation of AMPK gamma subunit by Cereblon inhibits AMPK activity
Yang, S., Jeon, S., Nguyen, T. V., Deshaies, R. J., Park, C., & Lee, K. M. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2020.118729 · Cited by 26 · see citing works
Self-citationTreatment of Lymphoid and Myeloid Malignancies by Immunomodulatory Drugs
Fuchs, O. (2018) · Cardiovascular & Haematological Disorders - Drug Targets · doi:10.2174/1871529x18666180522073855 · Cited by 26 · see citing works
The potential of inhibiting glutamine uptake as a therapeutic target for multiple myeloma
Giuliani, N., Chiu, M., Bolzoni, M., Accardi, F., Bianchi, M. G., Toscani, D., Aversa, F., & Bussolati, O. (2017) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2017.1279148 · Cited by 25 · see citing works
Baek, J.-H., Kim, M. S., Jung, H. R., Hwang, M.-S., Lee, C.-H., Han, D. H., Lee, Y., Yi, E. C., Im, S., Hwang, I., et al. (2023) · Experimental & Molecular Medicine · doi:10.1038/s12276-023-01036-7 · Cited by 23 · see citing works
Cereblon harnesses Myc-dependent bioenergetics and activity of CD8+ T lymphocytes
Hesterberg, R. S., Beatty, M. S., Han, Y., Fernandez, M. R., Akuffo, A. A., Goodheart, W. E., Yang, C., Chang, S., Colin, C., Alontaga, A. Y., et al. (2020) · Blood · doi:10.1182/blood.2019003257 · Cited by 22 · see citing works
Ji, H., Liu, D., Zhang, Z., et al. (2020) · The Plant Journal · doi:10.1111/tpj.14980 · Cited by 21 · see citing works
Acetylation: a new target for protein degradation in cancer
Crawford, C. E. W., & Burslem, G. M. (2025) · Trends in Cancer · doi:10.1016/j.trecan.2025.01.013 · Cited by 20 · see citing works
Pacifico, F., Mellone, S., D’Incalci, M., Stornaiuolo, M., Leonardi, A., & Crescenzi, E. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.115159 · Cited by 20 · see citing works
Karapurkar, J. K., Colaco, J. C., Suresh, B., Tyagi, A., Woo, S. H., Jo, W.-J., Ko, N. R., Singh, V., Hong, S., Oh, S. J., et al. (2024) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-024-05187-2 · Cited by 19 · see citing works
“To avoid non-specific binding of poly-ubiquitin molecules to MAST1 protein, the protein-bound agarose beads were washed with lysis buffer containing 300 mM NaCl as previously described [30].”
MethodWard, M. M. S. A., Abdallah, A. E., Zayed, M. F., et al. (2023) · Journal of Molecular Structure · doi:10.1016/j.molstruc.2023.137041 · Cited by 18 · see citing works
Kallistatin leads to cognition impairment via downregulating glutamine synthetase
Long, Y., Zhao, Z., Xie, W., Shi, J., Yang, F., Zhu, D., Jiang, P., Tang, Q., Zhou, T., Jiang, B., et al. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107145 · Cited by 18 · see citing works
Millrine, D., Tei, M., Gemechu, Y., & Kishimoto, T. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1611751113 · Cited by 18 · see citing works
“Given the literature (20, 21, 23, 24), we considered whether Rabex-5 is a substrate of CUL4A.”
BackgroundInfluentialTao, J., Yang, J., & Xu, G. (2018) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2018.11.058 · Cited by 18 · see citing works
Lian, Q., Gao, Y., Li, Q., He, X., Jiang, X., Pu, Z., & Xu, G. (2020) · The Protein Journal · doi:10.1007/s10930-020-09918-9 · Cited by 17 · see citing works
Komatsu, A., Iida, I., Nasu, Y., Ito, G., Harada, F., Kishikawa, S., Moss, S. J., Maeda, T., & Terunuma, M. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.101933 · Cited by 16 · see citing works
He, Q., Yang, M. G., Huang, J. L., Wu, W., Tang, K., Zhang, Y., Zhou, J., Ou, W., Xie, M., Liang, Y., et al. (2022) · British Journal of Anaesthesia · doi:10.1016/j.bja.2022.06.041 · Cited by 18 · see citing works
Jones, A. G., Aquilino, M., Tinker, R. J., Duncan, L., Jenkins, Z. A., Carvill, G. L., DeWard, S. J., Grange, D. K., Hajianpour, M. J., Halliday, B. J., et al. (2024) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2024.03.005 · Cited by 17 · see citing works
Zhou, L., & Xu, G. (2022) · Journal of Molecular Biology · doi:10.1016/j.jmb.2022.167457 · Cited by 17 · see citing works
Ortigosa, F., Valderrama‐Martín, J. M., Urbano-Gámez, J. A., García‐Martín, M. L., Ávila, C., Cánovas, F. M., & Cañas, R. A. (2020) · Plants · doi:10.3390/plants9040481 · Cited by 15 · see citing works
Heim, C., & Hartmann, M. D. (2022) · Acta Crystallographica Section D Structural Biology · doi:10.1107/s2059798322000092 · Cited by 20 · see citing works
Park, I., Phan, T. M., & Fang, J. (2021) · Cancers · doi:10.3390/cancers13205084 · Cited by 15 · see citing works
“In the presence of high levels of glutamine, glutamine synthetase (GS) is acetylated, followed by binding to the CRL4CRBN complex and subsequent ubiquitination and degradation by the proteasome [94].”
Background
- Authors
- Van Nguyen, T., Lee, J. E., Sweredoski, M. J., Yang, S.-J., Jeon, S.-J., Harrison, J. S., Yim, J.-H., Lee, S. G., Handa, H., Kuhlman, B., Jeong, J.-S., Reitsma, J. M., Park, C.-S., Hess, S., & Deshaies, R. J.
- Affiliations
- California Institute of Technology (US)
- Gwangju Institute of Science and Technology (KR)
- University of North Carolina at Chapel Hill (US)
- Korea Research Institute of Standards and Science (KR)
- Yonsei University (KR)
- Tokyo Medical University (JP)
- Corresponding author
- Deshaies, Raymond J.
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2016-03
- Volume
- 61
- Issue
- 6
- Pages
- 809-820
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC4889030
- OpenAlex
- W2299508065
- Cited by
- 177
- References
- 60
- Citations by year
- 2026: 8 · 2025: 18 · 2024: 15 · 2023: 9 · 2022: 27 · 2021: 24 · 2020: 20 · 2019: 11 · 2018: 13 · 2017: 23 · 2016: 8
- FWCI
- 9.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Scholarly Commons (University of the Pacific) (submittedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- Howard Hughes Medical Institute
- National Institute of General Medical Sciences (F32GM112308, R01GM065997, R01GM073960)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- glutamine synthetase, cereblon, lysine acetylation, protein degradation, immunomodulators, proteasome, ubiquitination
- MeSH terms
- Acetylation, Glutamine, Glutamate-Ammonia Ligase, Humans, Immunologic Factors, Lysine, Peptide Hydrolases, Thalidomide, Ubiquitin-Protein Ligases, Proteasome Endopeptidase Complex, Adaptor Proteins, Signal Transducing, Receptors, Interleukin-17, Ubiquitination, HEK293 Cells, Proteolysis
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