The DOI matches its Crossref record; 69 of the 69 references it cites were found in a registry or an index; 24 of the 40 sources its claims cite were checked for support.
Haploid genetic screens identify SPRING/C12ORF49 as a determinant of SREBP signaling and cholesterol metabolism
Open accessAbstract
The sterol-regulatory element binding proteins (SREBP) are central transcriptional regulators of lipid metabolism. Using haploid genetic screens we identify the S REB P R egulat in g G ene ( SPRING/C12ORF49 ) as a determinant of the SREBP pathway. SPRING is a glycosylated Golgi-resident membrane protein and its ablation in Hap1 cells, Hepa1-6 hepatoma cells, and primary murine hepatocytes reduces SREBP signaling. In mice, Spring deletion is embryonic lethal yet silencing of hepatic Spring expression also attenuates the SREBP response. Mechanistically, attenuated SREBP signaling in SPRING KO cells results from reduced SREBP cleavage-activating protein (SCAP) and its mislocalization to the Golgi irrespective of the cellular sterol status. Consistent with limited functional SCAP in SPRING KO cells, reintroducing SCAP restores SREBP-dependent signaling and function. Moreover, in line with the role of SREBP in tumor growth, a wide range of tumor cell lines display dependency on SPRING expression. In conclusion, we identify SPRING as a previously unrecognized modulator of SREBP signaling.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
Using three independent haploid genetic screens, this study identifies SPRING/C12ORF49 as a Golgi-resident regulator of SREBP signaling. SPRING loss reduces functional SCAP, attenuates SREBP2-dependent cholesterol metabolism in cells and mouse liver, and causes embryonic lethality in mice.
Key findings
- Three SREBP-focused haploid screens converged on a core set of 5 shared genes required for SREBP signaling: SREBF2, SCAP, MBTPS1, MBTPS2, and SPRING/C12ORF49.
- SPRING ablation reduced SREBP signaling in Hap1 cells, Hepa1-6 hepatoma cells, and primary murine hepatocytes; Hap1-SPRINGKO cells failed to induce HMGCR, LDLR, SQLE, and FASN upon sterol depletion and showed reduced surface LDLR and LDL uptake.
- Mechanistically, SPRINGKO cells had reduced SCAP protein and SCAP trapped in the Golgi irrespective of sterol status; reintroducing SCAP restored SREBP2-dependent signaling, LDL uptake, and de novo cholesterol biosynthesis.
- Spring deletion was embryonic lethal in mice, while hepatic Spring silencing reduced Srebf2 and targets Hmgcs, Hmgcr, Sqs, Dhcr24, Pcsk9, and Ldlr; in DepMap, SPRING emerged as a selective dependency in 337/342 evaluated cancer cell lines.
Methods
- Haploid genetic screens in Hap1 cells: an SQLE-mNeon FACS screen for cholesterol-dependent SQLE regulation, a FASNKO synthetic-lethality screen, and integration with a prior Andes virus SREBP-focused screen.
- CRISPR/Cas9 knockout and rescue experiments in Hap1, Hepa1-6, CHO-SCAP-eGFP, and primary mouse hepatocytes, with RNAseq, qPCR, immunoblotting, immunofluorescence, co-immunoprecipitation, protease protection, LDL uptake/surface LDLR FACS, and 13C2-acetate cholesterol synthesis mass spectrometry.
- Mouse studies used adenoviral hepatic Spring silencing in C57BL/6J mice and CRISPR/Cas9-generated Spring knockout mice; DepMap CRISPR/Cas9 lethality data were interrogated for SPRING dependency.
Limitations
- The paper states that SCAP localization experiments used cells stably overproducing SCAP-eGFP, which may mask effects on SCAP protein level, and that the cellular localization of the SCAP-SPRING interaction could not be formally established.
- The paper states that the limited effect of hepatic Spring silencing on SREBP1 signaling could be due to short experiment duration, residual Spring mRNA, or lack of dietary challenge; whether embryonic lethality relates to lipid metabolism and whether SPRING variation contributes to human lipid traits remain to be investigated.
- Evident from the text: the co-immunoprecipitation showed SPRING detected with SCAP but not enriched relative to total lysate, and the detailed mechanism by which SPRING regulates SCAP trafficking requires new sensitive quantitative assays.
Model-written summary. Check it against the paper before relying on it.
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Cites
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Verification
Claims the paper makes
24 of 40 cited sources checked · 14 supported · 1 flagged · accuracy not yet measured
- Findingown data
The strongest negative regulator of SQLE-mNeon found in the screen was the E3 ubiquitin ligase MARCH6 and its cognate E2 partner UBE2J2.
“Conversely, the strongest negative regulator of SQLE-mNeon found in our screen was the E3 ubiquitin ligase MARCH6, and its cognate E2 partner UBE2J2, which we have recently reported to be critical determinants of cholesterol-dependent degradation of SQLE25–27.”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [25] Hobbs, H. H., Russell, D. W., Brown, M. S. & Goldstein, J. L. The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein. Annu. Rev. Genet. 24, 133–170 (1990). source
- cites [26] Goldstein, J. L., Rawson, R. B. & Brown, M. S. Mutant mammalian cells as tools to delineate the sterol regulatory element-binding protein pathway for feedback regulation of lipid synthesis. Arch. Biochem. Biophys. 397, 139–148 (2002). source
- cites [27] Jae, L. T. et al. Deciphering the glycosylome of dystroglycanopathies using haploid screens for lassa virus entry. Science 340, 479–483 (2013). source
The paper’s main-text account of its haploid screen identifies factors involved in Lassa virus entry and dystroglycan glycosylation, not regulators of SQLE-mNeon. Searches for MARCH6, UBE2J2, SQLE-mNeon, and cholesterol-dependent SQLE degradation found no passage addressing the claim. (LLM, conf=0.78)
Experimental — accuracy not yet measured
- Premisecitation
The effect of hepatic Spring silencing on SREBP2 is similar to the phenotype observed in liver- or intestine-specific Scap knockout mice.
“The effect on SREBP2 is similar to the phenotype observed in liver- or intestine-specific Scap knockout mice46,55”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [46] Matsuda, M. et al. SREBP cleavage-activating protein (SCAP) is required for increased lipid synthesis in liver induced by cholesterol deprivation and insulin elevation. Genes Dev. 15, 1206–1216 (2001). source
- cites [55] McFarlane, M. R. et al. Scap is required for sterol synthesis and crypt growth in intestinal mucosa. J. Lipid Res. 56, 1560–1571 (2015). source
- Premisecitation
An intact SREBP2 pathway is functionally required to drive the SREBP1-controlled genetic program.
“the functional requirement of an intact SREBP2 pathway to drive the SREBP1-controlled genetic program53,56”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [53] Vergnes, L. et al. SREBP-2-deficient and hypomorphic mice reveal roles for SREBP-2 in embryonic development and SREBP-1c expression. J. Lipid Res. 57, 410–421 (2016). source
In “SREBP-2 influences limb development and SREBP-1 regulation” (p. 417), the paper says SREBP-2 is required for basal Srebf1c expression and for sterol regulation of many SREBP target genes. It does not establish a requirement for the entire SREBP-1-controlled program: Srebf1a is explicitly an exception. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [56] Rong, S. et al. Expression of SREBP-1c Requires SREBP-2-mediated Generation of a Sterol Ligand for LXR in Livers of Mice. Elife 6, S15 (2017). source
- Interpretationown data
The phenotype of SPRINGKO cells is highly reminiscent of cells lacking SCAP and liver-specific Scap knockout mice.
“This is highly reminiscent of what is observed in cells lacking SCAP45 and in liver-specific Scap knockout mice46.”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [45] Rawson, R. B., DeBose-Boyd, R., Goldstein, J. L. & Brown, M. S. Failure to cleave sterol regulatory element-binding proteins (SREBPs) causes cholesterol auxotrophy in Chinese hamster ovary cells with genetic absence of SREBP cleavage-activating protein. J. Biol. Chem. 274, 28549–28556 (1999). source
- cites [46] Matsuda, M. et al. SREBP cleavage-activating protein (SCAP) is required for increased lipid synthesis in liver induced by cholesterol deprivation and insulin elevation. Genes Dev. 15, 1206–1216 (2001). source
- Findingown data
Srebf1 and its target genes Fasn, Scd1, and Acc were unchanged upon hepatic Spring silencing.
“Notably, Srebf1 and its target genes Fasn, Scd1, and Acc were unchanged.”
Quote in the paperSubstantial claim
- Findingown data
The SREBP program could be restored by reintroducing SPRING in sterol-depleted Hap1-SPRINGKO cells.
“Importantly, the SREBP program could be restored by reintroducing SPRING in sterol-depleted Hap1-SPRINGKO cells (Fig. 3d).”
Quote in the paperSubstantial claim - Findingown data
The abnormal embryos were confirmed to be homozygous null mutants by PCR genotyping.
“The abnormal embryos were confirmed to be homozygous null mutants by PCR genotyping (Supplementary Fig. 5B, C).”
Quote in the paperSubstantial claim - Findingown data
No differences were observed in hepatic and plasma lipids in the hepatic Spring silencing experiment.
“In this experimental setting no differences were observed in hepatic and plasma lipids.”
Quote in the paperNot a substantial claim - Findingown data
mRNA and protein levels of SPRING were not sensitive to cellular sterol status.
“Notably, mRNA and protein levels of SPRING were not sensitive to the cellular sterol status.”
Quote in the paperNot a substantial claim - Findingown data
A total of 72 genes showed a synthetic genetic interaction in Hap1-FASNKO cells.
“A total of 72 genes showed a synthetic genetic interaction in Hap1-FASNKO cells (Fig. 1f).”
Quote in the paperSubstantial claim- Rests on an assumption: In the absence of FASN and fatty acid synthesis, Hap1 cells must rely on alternative survival pathways for acquiring fatty acids and growth.
- Findingown data
Mutation of the single predicted glycosylation site (Asn-67) abolished SPRING glycosylation.
“Further, mutation of the single predicated glycosylation site (Asn-67) abolished SPRING glycosylation (Fig. 5c).”
Quote in the paperNot a substantial claim - Findingown data
In the absence of SPRING, expression of SREBP-regulated target genes was refractory to sterol depletion.
“While Hap1-WT increased expression of a panel of SREBP-regulated target genes in response to sterol depletion, in the absence of SPRING the expression of these genes was refractory to this treatment.”
Quote in the paperSubstantial claim - Findingown data
In CHO cells devoid of Spring, SCAP-eGFP appeared trapped in the Golgi irrespective of the cellular sterol status.
“However, in CHO cells devoid of Spring, SCAP-eGFP appeared trapped in the Golgi irrespective of the cellular sterol status.”
Quote in the paperSubstantial claim - Findingown data
N-glycosidase (PNGase-F) removed glycans from SPRING protein.
“Consistent with glycosylation of SPRING, N-glycosidase (PNGase-F) removed glycans from SPRING protein (Supplementary Fig. 6C).”
Quote in the paperNot a substantial claim - Findingown data
Effective adenoviral-mediated silencing of hepatic Spring resulted in significant reduction of Srebf2 and downstream transcriptional targets Hmgcs, Hmgcr, Sqs, Dhcr24, Pcsk9, and Ldlr in refed mice.
“Under this setting, effective Spring silencing resulted in significant reduction of Srebf2 and a panel of its downstream transcriptional targets Hmgcs, Hmgcr, Sqs, Dhcr24, Pcsk9, and Ldlr (Fig. 4c).”
Quote in the paperSubstantial claim - Findingown data
These SREBP signature genes appeared to be non-essential in WT Hap1 cells.
“Notably, these genes appeared to be non-essential in WT Hap1 cells.”
Quote in the paperSubstantial claim - Findingown data
Proteolytic processing of SREBP2 can occur in the absence of SPRING.
“Notably, we found that proteolytic processing of SREBP2 can occur in the absence of SPRING.”
Quote in the paperSubstantial claim - Findingown data
A set of SREBP target genes including LDLR, ACSL1, ACSL3, and FABP5 displayed a synthetic interaction in Hap1-FASNKO cells.
“Additionally, a set of SREBP target genes including LDLR, ACSL1, ACSL3, and FABP5, that are implicated in lipid uptake, trafficking, and metabolism also displayed a synthetic interaction in Hap1-FASNKO cells (Supplementary Fig. 3A).”
Quote in the paperSubstantial claim - Findingown data
Heterozygous crosses of Spring(−/−) mice failed to produce viable homozygous knockout offspring.
“However, heterozygous crosses failed to produce viable homozygous knockout offspring (Fig. 4b).”
Quote in the paperSubstantial claim - Findingown data
SCAP can interact with SPRING when the two are over-expressed in a model system.
“We used a co-immunoprecipitation approach and found that SCAP can interact with SPRING when the two are over-expressed in a model system (Fig. 6a).”
Quote in the paperSubstantial claim - Findingown data
In Hap1-FASNKO cells, a prominent SREBP signature encompassing SREBF2, SCAP, MBTPS1, MBTPS2, and SPRING was apparent.
“Amongst these, a prominent SREBP signature encompassing the gene encoding SREBP2 itself, SREBF2, the genes encoding the core SREBP-activation machinery (SCAP, MBTPS1, and MBTPS2) and the uncharacterized gene SPRING were apparent in Hap1-FASNKO cells.”
Quote in the paperSubstantial claim - Findingown data
Integrating the three SREBP-focused haploid screens identifies a core set of 5 shared genes necessary for SREBP signaling: SREBF2, SCAP, MBTPS1, MBTPS2, and SPRING.
“When integrating the three SREBP-focused haploid screens we identify a core set of 5 shared genes necessary for SREBP signaling that next to SREBF2, SCAP, MBTPS1, MTBPS2 also includes SPRING (Fig. 1g).”
Quote in the paperSubstantial claim- Rests on an assumption: Any unknown SREBP regulator should be found in independent haploid genetic screens.
- Findingown data
Comparison of transcriptional profiles of Hap1-WT and Hap1-SPRINGKO cells confirmed aberrant activation of the SREBP pathway in Hap1-SPRINGKO cells.
“This comparison confirmed the aberrant activation of the SREBP pathway in Hap1-SPRINGKO cells.”
Quote in the paperSubstantial claim - Findingown data
Induction of ER stress by Tunicamycin, which promotes ATF6 translocation to the Golgi and subsequent proteolytic processing by S1P/S2P proteases, was intact in SPRINGKO cells, albeit with a small yet significant reduction.
“Importantly, induction of ER stress by Tunicamycin, which promotes ATF6 translocation to the Golgi and subsequent proteolytic processing by S1P/S2P proteases was intact, albeit we did observe a small yet significant reduction.”
Quote in the paperSubstantial claim - Findingown data
Introducing an N-terminal constitutively active SREBP2 transcriptional domain into Hap1-SPRINGKO cells restored basal and sterol-depletion-induced levels of SQLE.
“Yet this does not seem to be the case, as when we introduce an N-terminal constitutively active SREBP2 transcriptional domain into Hap1-SPRINGKO cells we were able to restore the basal and sterol-depletion-induced levels of SQLE (Fig. 2g).”
Quote in the paperSubstantial claim - Findingown data
The levels of chimeric SQLE-mNeon protein were subject to cholesterol-stimulated proteasomal degradation, similar to untagged SQLE.
“Moreover, similar to untagged SQLE, the levels of chimeric SQLE-mNeon protein were subject to cholesterol-stimulated proteasomal degradation (Supplementary Fig. 1B).”
Quote in the paperSubstantial claim - Findingown data
In transfected HeLa cells, SPRING predominantly co-localized with the Golgi marker GM130.
“In transfected HeLa cells SPRING was predominantly co-localized with the Golgi marker GM130 (Fig. 5b).”
Quote in the paperSubstantial claim - Findingown data
ER-localization of SCAP-eGFP could be restored in SPRINGKO cells grown in the presence of sterols by introducing back SPRING expression.
“Importantly, ER-localization of SCAP-eGFP could be restored in the SPRINGKO cells grown in the presence of sterols by introducing back SPRING expression.”
Quote in the paperSubstantial claim - Findingown data
Using the same approach, no interaction between SPRING and INSIG was detected.
“However, we point out that using the same approach we were unable to detect an interaction between SPRING and INSIG.”
Quote in the paperNot a substantial claim - Findingown data
Among known core SREBP activating genes identified as positive regulators of SQLE expression, the screen found an uncharacterized gene, C12ORF49, referred to as SPRING.
“Amongst the known core SREBP activating genes, identified as positive regulators of SQLE expression, we also found an uncharacterized gene, C12ORF49, which is further referred to as SREBP-Regulating Gene (SPRING).”
Quote in the paperSubstantial claim - Findingown data
SPRINGKDEL was largely retained in the ER, as evident by co-localization with VAPA.
“SPRINGKDEL was largely retained in the ER, as evident by co-localization with the ER marker protein VAMP-associated protein A (VAPA, Fig. 5e).”
Quote in the paperSubstantial claim - Findingown data
Basal ER-stress, as evaluated by expression of ATF6-driven genes and other ER stress-related genes, was not changed in cells lacking SPRING.
“Basal ER-stress, as evaluated by expression of ATF6-driven genes and other ER stress-related genes, was not changed in cells lacking SPRING.”
Quote in the paperSubstantial claim - Findingown data
Adenoviral-mediated silencing of hepatic Spring expression has limited effect on the SREBP1 pathway.
“with limited effect on the SREBP1 pathway”
Quote in the paperNot a substantial claim - Findingown data
In the DepMap panel, the top co-dependent genes with SPRING were those associated with the core SREBP machinery.
“Remarkably, in this panel of cell lines the top co-dependent genes with SPRING were those associated with the core SREBP machinery (Supplementary Fig. 8B), mirroring our haploid genetic screen results.”
Quote in the paperSubstantial claim - Findingown data
Genetic ablation of Spring in mice results in early embryonic lethality.
“Genetic ablation of Spring resulted in early embryonic lethality”
Quote in the paperSubstantial claim - Findingown data
Introduction of SCAP was sufficient to restore LDL uptake and de novo cholesterol biosynthesis in Hap1 SPRINGKO cells.
“Functionally, introduction of SCAP was sufficient to restore LDL uptake and de novo cholesterol biosynthesis (Fig. 6e, f and Supplementary Fig. 7B).”
Quote in the paperSubstantial claim - Findingown data
Adenoviral-mediated silencing of hepatic Spring expression markedly attenuates SREBP2 signaling in the liver.
“Using adenoviral-mediated silencing of hepatic Spring expression we found marked attenuation of SREBP2 signaling in the liver”
Quote in the paperSubstantial claim - Findingown data
A wide variety of human tumor cells display dependency on expression of a core set of SREBP-centered genes, including SPRING, for their growth.
“Our bioinformatic analysis suggests that a wide-variety of human tumor cells display dependency on expression of a core set of SREBP-centered genes, including SPRING, for their growth”
Quote in the paperNot a substantial claim - Findingown data
In the DepMap database of 342 cancer cell lines, SPRING expression emerged as a selective gene in 337/342 evaluated cell lines.
“Within the database of 342 cancer cell lines (27 distinct lineages) that were subjected to genome-wide CRISPR/Cas9 lethality, SPRING expression emerged as a selective gene in 337/342 of the evaluated cell lines (Supplementary Fig. 8A).”
Quote in the paperSubstantial claim - Findingown data
The ATF6-mediated stress response, which requires sequential proteolytic processing by S1P and S2P but does not require SCAP, is also reduced in the absence of SPRING.
“Our observation that the ATF6-mediated stress response - which like SREBP activation requires the sequential proteolytic processing by S1P and S2P yet does not require SCAP - is also reduced in the absence of SPRING provides support for this scenario and may explain reduced SCAP protein level in SPRINGKO cells.”
Quote in the paperSubstantial claim - Findingown data
Introducing SCAP into Hap1 SPRINGKO cells fully restored the SREBP2-mediated sterol-dependent response.
“In line with this idea we found that introducing SCAP into Hap1 SPRINGKO cells, similar to introducing back SPRING, fully restored the SREBP2-mediated sterol-dependent response (Fig. 6d).”
Quote in the paperSubstantial claim - Findingown data
Endogenous SCAP protein was reduced in Hap1 SPRINGKO cells.
“Remarkably, SCAP protein was reduced in Hap1 SPRINGKO cells.”
Quote in the paperSubstantial claim - Premisecitation
Hap1 cells tolerate loss of FASN, a canonical SREBP1-regulated gene.
“In a parallel screen, we leveraged our recent finding that Hap1 cells tolerate loss of the key de novo fatty acid synthesis enzyme, FASN, which is a canonical SREBP1-regulated gene24.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [24] Brockmann, M. et al. Genetic wiring maps of single cell protein states reveal an off-switch for GPCR signaling. Nature 546, 307–311 (2017) source
- Interpretationown data
SPRING/C12ORF49 is a previously unrecognized factor that governs SREBP activity in mammalian cells and in vivo in mice by controlling the level of functional SCAP.
“Using haploid genetic screens we identify the SREBP Regulating Gene (SPRING/C12ORF49) as a determinant of the SREBP pathway.”
- Also stated in: § Introduction · plain
“To identify unknown determinants of the SREBP pathway we applied a set of mammalian haploid genetic screens and report here the identification of the SREBP Regulating Gene SPRING (C12ORF49), as a previously unrecognized factor that governs SREBP activity in mammalian cells and in vivo in mice by controlling the level of functional SCAP.”
Quote in the paperSubstantial claim- Rests on an assumption: Any unknown SREBP regulator should be found in independent haploid genetic screens.
- Also stated in: § Introduction · plain
- Interpretationown data
The genetic distribution of offspring was consistent with loss of Spring being embryonic lethal.
“The genetic distribution of offspring was, in fact, consistent with loss of Spring being embryonic lethal and suggesting a critical role for Spring in mouse development.”
Quote in the paperSubstantial claim - Interpretationown data
SPRING is a determinant of SREBP activation in mammalian cells.
“Collectively, this set of experiments establishes SPRING as a determinant of SREBP activation in mammalian cells.”
Quote in the paperSubstantial claim - Interpretationown data
The first screen faithfully reports on cholesterol-dependent regulation of SQLE by the SREBP pathway.
“As such, this screen faithfully reports on cholesterol-dependent regulation of SQLE by the SREBP pathway.”
Quote in the paperSubstantial claim- Rests on an assumption: Any unknown SREBP regulator should be found in independent haploid genetic screens.
- Interpretationown data
The C-terminus of SPRING faces the Golgi lumen.
“In aggregate with our observation on SPRING glycosylation, these results indicate that the C-terminus of SPRING faces the Golgi lumen.”
Quote in the paperNot a substantial claim - Interpretationreasoning
In the absence of FASN, Hap1 cells depend on SREBP-dependent lipid uptake.
“These observations suggest that in the absence of FASN, Hap1 cells depend on SREBP-dependent lipid uptake and further support the idea that SPRING may be implicated in SREBP signaling.”
Quote in the paperSubstantial claim- Rests on an assumption: In the absence of FASN and fatty acid synthesis, Hap1 cells must rely on alternative survival pathways for acquiring fatty acids and growth.
- Interpretationown data
The three independent screens strongly point towards SPRING acting as a positive regulator of the SREBP pathway to govern lipid metabolism.
“In aggregate, our three independent screens strongly point towards SPRING acting as a positive regulator of the SREBP pathway to govern lipid metabolism.”
Quote in the paperSubstantial claim- Rests on an assumption: Any unknown SREBP regulator should be found in independent haploid genetic screens.
- Interpretationown data
Regulation of SREBP activity by SPRING requires its Golgi localization.
“Taken together, these results demonstrate that regulation of SREBP activity by SPRING requires its Golgi localization.”
Quote in the paperSubstantial claim - Interpretationreasoning
The phenotype of SPRINGKO cells is consistent with potential involvement of SPRING in the process of retrograde transport of SCAP.
“The phenotype of SPRINGKO cells is consistent with the potential involvement of SPRING in the process of retrograde transport of SCAP.”
Quote in the paperNot a substantial claim - Premisecitation
Upon delivery to the Golgi, the SCAP-SREBP complex is tethered to PAQR3.
“Upon delivery to the Golgi, the SCAP-SREBP complex is tethered to PAQR349.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [49] Xu, D. et al. PAQR3 modulates cholesterol homeostasis by anchoring Scap/SREBP complex to the Golgi apparatus. Nat. Commun. 6, 8100 (2015). source
Checked before — its earlier verdict is held back until a new check runs.
- Interpretationown data
Spring is required for embryonic development in mice.
“demonstrating that Spring is required for embryonic development in mice”
Quote in the paperSubstantial claim - Interpretationown data
Spring is a regulator of the SREBP program in vivo in mice.
“these results demonstrate that Spring is a regulator of the SREBP program in vivo in mice”
Quote in the paperSubstantial claim - Interpretationown data
SPRING is a previously unrecognized regulator of the SREBP program.
“we report here the identification of SPRING as a previously unrecognized regulator of the SREBP program”
Quote in the paperSubstantial claim - Interpretationreasoning
It is unlikely that SPRING directly acts as a retrieval adaptor protein because these sequences are also absent in SPRING.
“Yet as these are also absent in SPRING we find it unlikely that SPRING directly acts as a retrieval adaptor protein.”
Quote in the paperNot a substantial claim - Interpretationown data
A wide variety of tumor cells is dependent on SPRING expression for growth.
“This suggests that a wide-variety of tumor cells is dependent on SPRING expression for growth.”
Quote in the paperSubstantial claim - Interpretationreasoning
Mislocalization of SCAP to the Golgi in SPRINGKO cells likely results in depletion of functional SCAP in the ER.
“Mislocalization of SCAP to the Golgi in SPRINGKO cells likely results in depletion of functional SCAP in the ER, which is required at stoichiometric levels to support exit of SREBP towards the Golgi.”
Quote in the paperSubstantial claim - Interpretationreasoning
The primary lesion in SREBP signaling in SPRINGKO cells is narrowed to SCAP functionality.
“Accordingly, we have narrowed the primary lesion in SREBP signaling in SPRINGKO cells to SCAP functionality.”
Quote in the paperSubstantial claim
- It may state two separate claims as one. 29
- Probably not a substantial claim. 19
It may state two separate claims as one.
InterpretationreasoningSensitivity to Endo-H together with Golgi localization suggests SPRING is present in the cis/medial Golgi, where the SCAP-SREBP-S1P machinery is located.
“Together with the observed localization of SPRING in the Golgi (Fig. 5b), sensitivity to Endo-H suggests that SPRING is present in the cis/medial Golgi, which is where the SCAP-SREBP-S1P machinery is located32,33.”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [32] Nohturfft, A., DeBose-Boyd, R. A., Scheek, S., Goldstein, J. L. & Brown, M. S. Sterols regulate cycling of SREBP cleavage-activating protein (SCAP) between endoplasmic reticulum and Golgi. Proc. Natl Acad. Sci. USA 96, 11235–11240 (1999). source
The citation is attached to the proposed location of the SCAP–SREBP–S1P machinery, not to SPRING’s localization. The Discussion says the compartment containing active S1P is unknown and describes SREBP cleavage as occurring in a pre-Golgi compartment; the Results say most SCAP resides in the ER at steady state. These passages do not place the machinery in the cis/medial Golgi. (LLM, conf=0.85)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured - cites [33] DeBose-Boyd, R. A. et al. Transport-dependent proteolysis of SREBP: relocation of site-1 protease from Golgi to ER obviates the need for SREBP transport to Golgi. Cell 99, 703–712 (1999). source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationThe entry of Andes viruses into target cells critically depends on SREBP signaling and on the presence of cholesterol in the host-cell membrane.
“Previously, we have reported a haploid genetic screen that revealed that the entry of Andes viruses into target cells critically depends on SREBP signaling and on the presence of cholesterol in the host-cell membrane29.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [29] Kleinfelter, L. M. et al. Haploid genetic screen reveals a profound and direct dependence on cholesterol for hantavirus membrane fusion. MBio 6, e00801 (2015). source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationSREBP2 primarily regulates genes linked to cholesterol synthesis and uptake, including HMGCR, SQLE, and LDLR.
“In contrast, SREBP2 is primarily implicated in the regulation of genes linked to cholesterol synthesis and uptake, including those encoding for the rate-limiting enzymes in cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and squalene epoxidase (SQLE), and the low-density lipoprotein receptor (LDLR)6.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [6] Hua, X. et al. SREBP-2, a second basic-helix-loop-helix-leucine zipper protein that stimulates transcription by binding to a sterol regulatory element. Proc. Natl Acad. Sci. USA 90, 11603–11607 (1993). source
The paper’s available text reports that SREBP-2 binds a sterol regulatory element found in the LDL receptor and HMG-CoA synthase promoters and activates reporters containing that element. It supports a role in cholesterol-related gene regulation, but does not identify HMG-CoA reductase (HMGCR) or squalene epoxidase (SQLE) as targets, or establish that these genes are SREBP-2’s primary regulatory focus. HMG-CoA synthase is not HMGCR. (LLM, conf=0.89)
Experimental — accuracy not yet measured
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationSREBPs contain an SRE in their promoter and induce their own expression in a positive feedback mechanism.
“As SREBPs contain an SRE in their promoter region, they induce their own expression in a positive feedback mechanism4,18.”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [4] Horton, J. D., Goldstein, J. L. & Brown, M. S. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest. 109, 1125–1131 (2002). source
The ‘Transcriptional regulation of SREBP genes’ section says that SREs in the enhancer/promoters of SREBP-1c and SREBP-2 enable nuclear SREBPs to activate transcription of their own genes. It does not extend this feedback mechanism to SREBP-1a, which it describes as constitutively expressed at low levels, so the claim is broader than the source supports. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [18] Horton, J. D. et al. Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc. Natl Acad. Sci. USA 100, 12027–12032 (2003). source
The introductory passage says SREBPs bind sterol response elements in the promoters of target genes, but it does not identify an SRE in an SREBP gene promoter or describe self-induction. The Results describe feedback through Insig-1, not positive feedback on SREBP expression. Searches for SREBP promoter autoregulation and positive feedback found no passage establishing the attributed mechanism. (LLM, conf=0.72)
Experimental — accuracy not yet measured
Probably not a substantial claim.
PremisecitationSREBPs are central transcriptional regulators of lipid metabolism.
“The sterol-regulatory element binding proteins (SREBP) are central transcriptional regulators of lipid metabolism.”
- Also stated in: § Introduction · plain
“The sterol-regulatory element binding proteins (SREBPs) are a family of transcription factors that control all facets of lipid metabolism by regulating the expression of a panel of genes that contain a sterol regulatory element (SRE) in their respective promoter regions2–4.”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [2] Goldstein, J. L., DeBose-Boyd, R. A. & Brown, M. S. Protein sensors for membrane sterols. Cell 124, 35–46 (2006). source
- cites [3] Jeon, T.-I. & Osborne, T. F. SREBPs: metabolic integrators in physiology and metabolism. Trends Endocrinol. Metab. 23, 65–72 (2012). source
- cites [4] Horton, J. D., Goldstein, J. L. & Brown, M. S. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest. 109, 1125–1131 (2002). source
- Also stated in: § Introduction · plain
Probably not a substantial claim. It may state two separate claims as one.
PremisecitationA drop in ER cholesterol leads to a conformational change in SCAP, dissociation from INSIG, and COPII-mediated trafficking of the SCAP-SREBP complex to the Golgi.
“A drop in cholesterol in the ER membrane leads to a conformational change in SCAP11,12, which leads to dissociation from INSIG and facilitates COPII-mediated trafficking of the SCAP-SREBP complex to the Golgi13–15.”
Quote in the paperSubstantial claim2 of 5 sources checked- cites [11] Brown, A. J., Sun, L., Feramisco, J. D., Brown, M. S. & Goldstein, J. L. Cholesterol addition to ER membranes alters conformation of SCAP, the SREBP escort protein that regulates cholesterol metabolism. Mol. Cell 10, 237–245 (2002). source
- cites [12] Radhakrishnan, A., Goldstein, J. L., McDonald, J. G. & Brown, M. S. Switch-like control of SREBP-2 transport triggered by small changes in ER cholesterol: a delicate balance. Cell Metab. 8, 512–521 (2008). source
- cites [13] Gong, Y. et al. Sterol-regulated ubiquitination and degradation of Insig-1 creates a convergent mechanism for feedback control of cholesterol synthesis and uptake. Cell Metab. 3, 15–24 (2006). source
- cites [14] Engelking, L. J. et al. Schoenheimer effect explained–feedback regulation of cholesterol synthesis in mice mediated by Insig proteins. J. Clin. Invest. 115, 2489–2498 (2005). source
- cites [15] Espenshade, P. J., Li, W.-P. & Yabe, D. Sterols block binding of COPII proteins to SCAP, thereby controlling SCAP sorting in ER. Proc. Natl Acad. Sci. USA 99, 11694–11699 (2002). source
Probably not a substantial claim.
PremisecitationUnder sufficient cellular sterols, SREBPs are retained in the ER through formation of a tripartite complex with SCAP and INSIG1/2.
“Under conditions of sufficient cellular sterols, SREBPs are retained in the ER through formation of a tripartite complex with the sterol-sensing SREBP cleavage-activating protein (SCAP)7,8, and the ER anchor proteins insulin-induced genes 1 and 2 (INSIG1 and 2)9,10.”
Quote in the paperSubstantial claim3 of 4 sources checked- cites [7] Hua, X., Nohturfft, A., Goldstein, J. L. & Brown, M. S. Sterol resistance in CHO cells traced to point mutation in SREBP cleavage-activating protein. Cell 87, 415–426 (1996). source
The Discussion describes SCAP as a component of sterol-regulated SREBP cleavage, and the paper describes a possible sterol-sensing region in SCAP. It does not establish that sterols retain SREBPs in the ER through a SCAP–INSIG tripartite complex. The citing sentence assigns the INSIG proteins to separate citations. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [8] Sakai, J. et al. Identification of complexes between the COOH-terminal domains of sterol regulatory element-binding proteins (SREBPs) and SREBP cleavage-activating protein. J. Biol. Chem. 272, 20213–20221 (1997). source
The Abstract reports that sterol-replete SREBPs remain in ER membranes and that SREBPs form a complex with SCAP. The discussion of Fig. 2 says this complex persists under both sterol depletion and repletion, so the paper does not establish that forming it causes sterol-dependent retention. It does not describe INSIG1/2 as members of a tripartite complex; the citing sentence assigns INSIG1/2 separate citations. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [9] Yang, T. et al. Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER. Cell 110, 489–500 (2002). source
- cites [10] Yabe, D., Brown, M. S. & Goldstein, J. L. Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins. Proc. Natl Acad. Sci. USA 99, 12753–12758 (2002). source
It may state two separate claims as one.
PremisecitationThe interaction between SCAP and PAQR3 anchors the complex to the Golgi and is necessary to support proteolytic activation of SREBP and hepatic lipid synthesis.
“The interaction between SCAP and PAQR3 anchors the complex to the Golgi and is necessary to support proteolytic activation of SREBP and hepatic lipid synthesis.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [49] Xu, D. et al. PAQR3 modulates cholesterol homeostasis by anchoring Scap/SREBP complex to the Golgi apparatus. Nat. Commun. 6, 8100 (2015). source
Probably not a substantial claim. It may state two separate claims as one.
PremisecitationCleavage by S1P is a prerequisite to release SCAP for COPI-mediated retrograde transport to the ER; pharmacological or genetic inhibition of this process prevents SCAP retrograde trafficking and directs SCAP towards lysosomal degradation.
“Cleavage by S1P is also a perquisite to release SCAP for COPI-mediated retrograde transport to the ER, as pharmacological or genetic inhibition of this process prevents SCAP retrograde trafficking, and instead directs SCAP towards lysosomal degradation48.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [48] Shao, W. & Espenshade, P. J. Sterol regulatory element-binding protein (SREBP) cleavage regulates Golgi-to-endoplasmic reticulum recycling of SREBP cleavage-activating protein (SCAP). J. Biol. Chem. 289, 7547–7557 (2014). source
The Discussion states that SREBP cleavage by S1P is required for SCAP to recycle from the Golgi to the ER; without cleavage, SCAP is ultimately degraded in the lysosome. The paper says SCAP “likely” returns in COPI-coated vesicles, so the claim overstates COPI-mediated transport as established. No page numbers are provided in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationGenetic variation in components of the SREBP genetic program, such as LDLR, PCSK9, and HMGCR, is associated with lipid traits in humans.
“genetic variation in components of the SREBP genetic program, such as in the LDLR, PCSK9, and HMGCR, is associated with lipid traits in humans57”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [57] Global Lipids Genetics Consortium. et al. Discovery and refinement of loci associated with lipid levels. Nat. Genet. 45, 1274–1283 (2013). source
The Introduction reports associations between human genetic variation and blood lipid levels, and the Results section on initial fine-mapping identifies a lipid-associated locus near PCSK9. The passages do not establish the claimed associations for LDLR and HMGCR or identify these genes as components of an SREBP genetic program; searches for those terms found no supporting passage. Page numbers are unavailable in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measured
It may state two separate claims as one.
Findingown dataIn control CHO-SCAP-eGFP cells grown in sterol-containing media, SCAP-eGFP was predominantly located in the ER and localization markedly shifted towards the Golgi upon sterol-depletion.
“In control cells grown in sterol-containing media SCAP-eGFP was predominantly located in the ER and localization markedly shifted towards the Golgi upon sterol-depletion (Fig. 6b and Supplementary Fig. 7A).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataAbnormally developed embryos at day 7.5 dpc were observed; these embryos were smaller and showed a poorly developed amniotic cavity and allantois.
“We did observe abnormally developed embryos at day 7.5 dpc. These embryos were smaller and showed a poorly developed amniotic cavity and allantois in comparison with the adjacent to normally developing embryos in the mouse uterine horn.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Findingown dataSpring is ubiquitously expressed in mouse tissues with slightly higher expression in the liver and kidney.
“Spring is ubiquitously expressed in mouse tissues with slightly higher expression in the liver and kidney (Supplementary Fig. 5A).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataHap1 cells lacking SPRING had reduced protein levels of SREBP targets SQLE, SQS, and INSIG1 under basal culture conditions and were unable to increase abundance of these under sterol-depletion.
“Cells lacking SPRING had reduced protein levels of the SREBP targets SQLE, SQS, and INSIG1 under basal culture conditions, and were unable to increase abundance of these under sterol-depletion condition.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataThe first screen identified strong enrichment of gene-trap insertions in the SQLE locus in the mNeonLOW population, alongside similar enrichment in SCAP, MBTPS1, MBTPS2, and SREBF2.
“Validating our screening approach, we identified strong enrichment of gene-trap insertions in the SQLE locus in the mNeonLOW population, alongside a similar enrichment in the established positive regulators of the SREBP pathway SCAP, MBTPS1, MBTPS2, and SREBF2 itself (Fig. 1e).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataSPRING-V5 was refractory to tryptic digestion, unlike LDLR-HA, and permeabilization with Triton X-100 rendered SPRING-V5 sensitive.
“Unlike LDLR-HA, which has its C-terminus exposed to the cytoplasm and is hence sensitive to tryptic digestion, SPRING-V5 was refractory (Fig. 5d). Permeabilization of cellular membranes with Triton X-100 rendered SPRING-V5 sensitive to tryptic digestion.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataThe SQLE-mNeon fusion protein level was low in Hap1-SQLE-mNeon cells cultured in sterol-containing medium and markedly increased upon sterol-depletion.
“Consistent with SREBP-dependent regulation of SQLE expression, the level of the SQLE-mNeon fusion protein was low in Hap1-SQLE-mNeon cells when cultured in sterol-containing medium yet was markedly increased upon sterol-depletion (Fig. 1b, c).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataIn Hap1-SPRINGKO cells, basal mRNA expression of SREBP transcriptional targets HMGCR, LDLR, SQLE, and FASN was reduced and the response to sterol-depletion was largely abrogated.
“Similarly, in contrast to control Hap1 cells which, as expected, robustly increased the mRNA expression of the SREBP-transcriptional targets HMGCR, LDLR, SQLE, and FASN in response to sterol-depletion, in Hap1-SPRINGKO cells basal expression of these genes was reduced and the response to sterol-depletion was largely abrogated.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataHap1-SPRINGKO cells exhibited markedly reduced levels of surface LDLR protein and failed to increase LDL uptake under sterol-deprived conditions.
“As a functional consequence, Hap1-SPRINGKO cells exhibited markedly reduced levels of surface LDLR protein and failed to increase LDL uptake under sterol-deprived conditions (Fig. 2c, d and Supplemental Fig. 2E).”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Findingown dataThe screen also identified INSIG1, an established negative regulator of the SREBP pathway.
“Additionally, as expected our screen also identified INSIG1, an established negative regulator of the SREBP pathway.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataAbsence of Spring profoundly reduced the precursor and mature protein level of SREBP2, and consequentially the level of its target genes, without a change in the level or localization of Site 1 Protease.
“However, we observed that absence of Spring profoundly reduced the precursor and mature (i.e., processed) protein level of SREBP2, and consequentially the level of its target genes in the absence of a change in the level or localization of Site 1 Protease (Supplementary Fig. 2B).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataSPRING glycosylation remained Endo-H-sensitive, unlike LDLR.
“We observed that unlike LDLR, SPRING glycosylation remained Endo-H-sensitive (Supplementary Fig. 6D).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataWT SPRING rescued sterol-dependent regulation of SQLE when introduced into Hap1-SPRINGKO cells, whereas SPRINGKDEL failed to do so.
“In contrast to WT SPRING, which could rescue sterol-dependent regulation of SQLE when introduced into Hap1-SPRINGKO cells, SPRINGKDEL failed to do so (Fig. 5f).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataSPRING is associated with cellular membranes and is not a secreted protein.
“We first considered the possibility that SPRING may be a secreted protein. However, our analysis indicates that this is not the case, but that SPRING is associated with cellular membranes (Supplementary Fig. 6A, B).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Premiseown dataSPRING encodes a 205 amino acid protein with no apparent homology to other proteins and is predicted to have a possible signal peptide, a single transmembrane-spanning domain, and a cysteine-rich motif.
“SPRING encodes for a 205 amino acid protein with no apparent homology to other proteins and is predicted to have a possible signal peptide, a single transmembrane-spanning domain, and a cysteine-rich motif (Fig. 5a).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Interpretationown dataSpring regulates SREBP signaling in vivo and has a crucial physiological role during embryogenesis.
“These results provide an indication that Spring regulates SREBP signaling in vivo and has a crucial physiological role during embryogenesis.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationThe final step in the SCAP-SREBP cycle is COPI-mediated retrograde transport of SCAP from the Golgi to the ER, allowing SCAP to reassociate with newly synthesized SREBPs and INSIGs in the ER.
“The final step in the SCAP-SREBP cycle is the less-well understood COPI-mediated retrograde transport of SCAP from the Golgi to the ER, which allows SCAP to reiteratively associate with newly synthesized SREBPs and INSIGs in the ER19.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [19] Takashima, K. et al. COPI-mediated retrieval of SCAP is crucial for regulating lipogenesis under basal and sterol-deficient conditions. J. Cell. Sci. 128, 2805–2815 (2015). source
Checked before — its earlier verdict is held back until a new check runs.
It may state two separate claims as one.
Interpretationown dataThe S1P/S2P axis is not globally abrogated in cells lacking SPRING and can still respond to physiological cues.
“This suggests that the S1P/S2P axis is not globally abrogated in cells lacking SPRING and can still respond to physiological cues.”
Quote in the paperSubstantial claimProbably not a substantial claim. It may state two separate claims as one.
PremisecitationSQLE is a rate-limiting enzyme in cholesterol biosynthesis and a bona fide transcriptional target of SREBP2.
“In the first screen, we evaluated the cholesterol-dependent regulation of SQLE, a rate-limiting enzyme in cholesterol biosynthesis and a bona fide transcriptional target of SREBP220,21.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [20] Sharpe, L. J. & Brown, A. J. Controlling cholesterol synthesis beyond 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). J. Biol. Chem. 288, 18707–18715 (2013). source
- cites [21] Howe, V., Sharpe, L. J., Prabhu, A. V. & Brown, A. J. New insights into cellular cholesterol acquisition: promoter analysis of human HMGCR and SQLE, two key control enzymes in cholesterol synthesis. Biochim Biophys. Acta Mol. Cell Biol. Lipids 1862, 647–657 (2017). source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationIn the Golgi, SREBP is proteolytically activated through sequential cleavage by S1P and S2P (MBTPS1 and MBTPS2), releasing the transcriptionally active N-terminal domain.
“In the Golgi, SREBP is proteolytically activated through sequential cleavage by the proteases S1P and S2P16,17 (encoded by MBTPS1 and MBTPS2), which release the transcriptionally active N-terminal domain of SREBP.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [16] Duncan, E. A., Brown, M. S., Goldstein, J. L. & Sakai, J. Cleavage site for sterol-regulated protease localized to a leu-Ser bond in the lumenal loop of sterol regulatory element-binding protein-2. J. Biol. Chem. 272, 12778–12785 (1997). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [17] Duncan, E. A., Davé, U. P., Sakai, J., Goldstein, J. L. & Brown, M. S. Second-site cleavage in sterol regulatory element-binding protein occurs at transmembrane junction as determined by cysteine panning. J. Biol. Chem. 273, 17801–17809 (1998). source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisenone givenSPRING is a Golgi-resident glycosylated membrane protein and together with its orthologs forms an uncharacterized protein family (Pfam UPF0454) with no substantial homology with other human proteins.
“SPRING is a Golgi-resident glycosylated membrane protein and together with its orthologs forms an uncharacterized protein family (Pfam UPF0454), which bears no substantial homology with other human proteins.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Interpretationown dataSPRING is a Golgi-resident factor required for maintaining SCAP function, and loss of SPRING results in functional depletion of SCAP in the ER and attenuation of SREBP signaling.
“Collectively, our in vitro and in vivo findings support the idea that SPRING is a Golgi-resident factor required for maintaining SCAP function, and that loss of SPRING results in functional depletion of SCAP in the ER and attenuation of SREBP signaling (Supplementary Fig. 9).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
InterpretationreasoningEctopic over-expression of SCAP rescues SREBP signaling in SPRINGKO cells, in line with functional depletion of SCAP in the ER.
“Consequentially, ectopic over-expression of SCAP rescues SREBP signaling in SPRINGKO cells, in line with functional depletion of SCAP in the ER.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataThe primary phenotype of cells lacking SPRING is decreased basal levels of precursor and mature SREBPs and SREBP signaling, and an inability to enhance SREBP signaling to mount a homeostatic response to sterol-depletion.
“We found that the primary phenotype of cells lacking SPRING is decreased basal levels of precursor and mature SREBPs and SREBP signaling, and an inability to enhance SREBP signaling so as to mount a homeostatic response to sterol-depletion.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataIn the adenoviral experiment, one mouse was excluded as the majority of the measured values were identified as outliers (Grubbs test, α = 0.1).
“In the adenoviral experiment, one mouse was excluded as the majority of the measured values were identified as outliers (Grubbs test, α = 0.1).”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenAll measurements were taken from distinct samples.
“All measurements were taken from distinct samples.”
Quote in the paperNot a substantial claimProbably not a substantial claim.
Study design and conductnone givenProper genome editing in all individual clones was confirmed by sequencing.
“Proper genome editing in all individual clones was confirmed by sequencing.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
PremisecitationThe embryonic lethality associated with Spring ablation is similar to that observed in mouse models of Srebf1 and Srebf2 deletion, although in those models embryonic lethality is not absolute.
“The embryonic lethality associated with Spring ablation is similar to that observed in mouse models of Srebf1 and Srebf2 deletion53,54, albeit in these models embryonic lethality is not absolute.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [53] Vergnes, L. et al. SREBP-2-deficient and hypomorphic mice reveal roles for SREBP-2 in embryonic development and SREBP-1c expression. J. Lipid Res. 57, 410–421 (2016). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [54] Shimano, H. et al. Elevated levels of SREBP-2 and cholesterol synthesis in livers of mice homozygous for a targeted disruption of the SREBP-1 gene. J. Clin. Invest. 100, 2115–2124 (1997). source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenAll plasmids were verified by sequencing.
“All plasmids were verified by sequencing”
Quote in the paperNot a substantial claimProbably not a substantial claim. It may state two separate claims as one.
PremisecitationRetrieval of proteins to the ER is classically dependent on the presence of a C-terminus -KKXX or -KDEL sequence, both of which are absent in SCAP.
“Retrieval of proteins to the ER is classically dependent on the presence of a C-terminus -KKXX or -KDEL sequence34, both of which are absent in SCAP.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [34] Munro, S. & Pelham, H. R. A C-terminal signal prevents secretion of luminal ER proteins. Cell 48, 899–907 (1987). source
The paper relies on this without support.
Any unknown SREBP regulator should be found in independent haploid genetic screens.
“Using this approach, we interrogated SREBP signaling in an unbiased manner reasoning that any unknown regulator should be found in independent screens.”
The paper relies on this without support.
In the absence of FASN and fatty acid synthesis, Hap1 cells must rely on alternative survival pathways for acquiring fatty acids and growth.
“We reasoned that in the absence of FASN and fatty acid synthesis Hap1 cells must rely on alternative survival pathways for acquiring fatty acids and growth.”
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?
In plasma, total cholesterol and triglycerides are lower in all mice with the exception that triglycerides are largely unchanged in Spring LKO.
“In plasma, (iii) total cholesterol and triglycerides are lower in all mice with the only exception being that the latter is largely unchanged in Spring LKO.”
From Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans (2023) · cites this paper as [10]
The Results section (‘Spring attenuates hepatic SREBP signaling in vivo’; page unavailable) reports no differences in plasma lipids after hepatic Spring silencing, contrary to the claimed reductions. It also says constitutive Spring-knockout mice could not be studied because of early embryonic lethality. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredAblation of Scap, Mbtps1, and Spring results in decreased cholesterol synthesis in isolated primary hepatocytes.
“Moreover, (iv) ablation of all 3 genes results in decreased cholesterol synthesis in isolated primary hepatocytes”
From Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans (2023) · cites this paper as [10]
The Results (‘SPRING is a determinant of the SREBP pathway in cells’; page unavailable) report that loss of Spring attenuated SREBP activity in primary mouse hepatocytes. But the cholesterol-synthesis assay was performed in Hap1 cells (Methods, ‘Cholesterol synthesis assay’; page unavailable), and the copy does not report decreased cholesterol synthesis after ablation of Scap, Mbtps1, and Spring in isolated primary hepatocytes. (LLM, conf=0.88)
Experimental — accuracy not yet measuredRestoration of SREBP function in Hap1-SpringKO cells occurs when SCAP is introduced.
“This contrasts with the restoration of SREBP function in these cells when SCAP is introduced10.”
From Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans (2023) · cites this paper as [10]
SPRING is a post-transcriptional regulator of SREBP activation.
“We recently identified SPRING as a post-transcriptional regulator of SREBP activation.”
From Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans (2023) · cites this paper as [10]
In the liver, cholesterol levels are lower in Scap and Spring mice, but unchanged in Mbtps1 mice.
“In the liver (i) cholesterol levels are lower in Scap and Spring mice, but unchanged in Mbtps1 mice”
From Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans (2023) · cites this paper as [10]
Global ablation of Spring and Mbtps1 in mice is embryonically lethal.
“Additionally, while global ablation of Spring and Mbtps1 in mice is embryonically lethal10,21”
From Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans (2023) · cites this paper as [10]
In the liver, triglyceride levels are lower in Scap, Mbtps1, and Spring mice.
“and (ii) triglyceride levels are lower in all three”
From Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans (2023) · cites this paper as [10]
Short-term adenovirus-mediated hepatic silencing of Spring mildly attenuates the SREBP-dependent postprandial transcriptional response.
“We have shown that short-term adenovirus-mediated hepatic silencing of Spring mildly attenuates the SREBP-dependent postprandial transcriptional response10.”
From Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans (2023) · cites this paper as [10]
Constitutive deletion of Mbtps1, Scap, or Spring leads to in utero lethality.
“Similarly, constitutive deletion of either Mbtps121, Scap31, or Spring10 leads to in utero lethality.”
From Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans (2023) · cites this paper as [10]
Ablation of Scap, Mbtps1, and Spring uniformly reduced the expression of Srebf1 and Srebf2 target genes.
“and (v) uniformly reduced the expression of Srebf1 and Srebf2 target genes”
From Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans (2023) · cites this paper as [10]
In cultured cells, SPRING is implicated in the retrograde transport of SCAP.
“We and others have proposed that, in cultured cells, SPRING is implicated in two important regulatory steps in the SREBP pathway, i.e. the retrograde transport of SCAP and in regulating the activity of S1P10–13.”
From Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans (2023) · cites this paper as [10]
Cells lacking SPRING have a functional depletion of SCAP in the ER due to impaired retrograde trafficking.
“Briefly, cells lacking SPRING have a functional depletion of SCAP in the ER due to its impaired retrograde trafficking10.”
From Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans (2023) · cites this paper as [10]
In cultured cells, SPRING is implicated in regulating the activity of S1P.
“We and others have proposed that, in cultured cells, SPRING is implicated in two important regulatory steps in the SREBP pathway, i.e. the retrograde transport of SCAP and in regulating the activity of S1P10–13.”
From Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans (2023) · cites this paper as [10]
The SPRING cysteine-rich domain is necessary and sufficient for interacting with S1P and SCAP, and for promoting S1P proteolytic maturation and restoration of SREBP signaling in SPRINGKO cells.
“which is both necessary and sufficient for interacting with S1P12–14 and SCAP10, and for promoting S1P proteolytic maturation and restoration of SREBP signaling in SPRINGKO cells14”
From Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans (2023) · cites this paper as [10]
Expression of Cre-recombinase in the Spring(fl/fl) model results in excision of exons 2-5.
“Expression of Cre-recombinase results in excision of exons 2-5.”
From Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans (2023) · cites this paper as Loregger et al. [10]
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.
Different intervals before fasting in the mouse experiment
MinorThe Fig. 4 caption says mice were fasted 7 days after adenoviral injection, whereas the Methods say fasting began 8 days after injection.
“After 7 days, mice were fasted overnight and subsequently refed for 6 h.”
“8 days later, mice were fasted (overnight) for 16 h and then refed a standard chow diet for an additional 6 h.”
Citations
Cites
SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver
Horton, J. D., Goldstein, J. L., & Brown, M. S. (2002) · Journal of Clinical Investigation · doi:10.1172/jci15593 · Cited by 4,794
The unfolded protein response: controlling cell fate decisions under ER stress and beyond
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Metadata
- Authors
- Loregger, A., Raaben, M., Nieuwenhuis, J., Tan, J. M. E., Jae, L. T., van den Hengel, L. G., Hendrix, S., van den Berg, M., Scheij, S., Song, J.-Y., Huijbers, I. J., Kroese, L. J., Ottenhoff, R., van Weeghel, M., van de Sluis, B., Brummelkamp, T., & Zelcer, N.
- Affiliations
- Amsterdam University Medical Centers (NL)
- The Netherlands Cancer Institute (NL)
- Amsterdam UMC Location University of Amsterdam (NL)
- University Medical Center Groningen (NL)
- Austrian Academy of Sciences (AT)
- Corresponding author
- Brummelkamp, Thijn
- Zelcer, Noam
- ORCID
- Venue
- Nature Communications
- Published
- 2020-02-28
- Volume
- 11
- Issue
- 1
- Pages
- 1128-1128
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC7048761
- OpenAlex
- W3009218725
- Semantic Scholar
- 91d9751a1121b4658ac40684f8a1a9f2aebea648
- Cited by
- 51
- References
- 69
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 7 · 2023: 7 · 2022: 9 · 2021: 7 · 2020: 5
- FWCI
- 2.22
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion, cc-by)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
- Funders
- Hartstichting (2016T015, 2013T111)
- KWF Kankerbestrijding (NKI-2015–7609)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (016.170.033, 016.176.643)
- Oncode Institute ; Cancer Genomics Center
- Ara Parseghian Medical Research Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- SREBP signaling, cholesterol metabolism, SCAP, Golgi apparatus, lipid metabolism, embryonic lethality, hepatocytes
- MeSH terms
- Animals, Cell Line, Cholesterol, Endoplasmic Reticulum, Golgi Apparatus, Haploidy, Humans, Liver, Membrane Glycoproteins, Membrane Proteins, Mice, Inbred C57BL, Signal Transduction, Gene Expression, Hepatocytes, Embryonic Development, Intracellular Signaling Peptides and Proteins, Lipid Metabolism, Mice, Sterol Regulatory Element Binding Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-11-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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