The DOI matches its Crossref record; 43 of the 43 references it cites were found in a registry or an index; 1 of the 30 sources its claims cite were checked for support.
Ubiquitin-specific Peptidase 8 (USP8) Regulates Endosomal Trafficking of the Epithelial Na+ Channel*
Open accessAbstract
Ubiquitination plays a key role in trafficking of the epithelial Na(+) channel (ENaC). Previous work indicated that ubiquitination enhances ENaC endocytosis and sorting to lysosomes for degradation. Moreover, a defect in ubiquitination causes Liddle syndrome, an inherited form of hypertension. In this work, we identified a role for USP8 in the control of ENaC ubiquitination and trafficking. USP8 increased ENaC current in Xenopus oocytes and collecting duct epithelia and enhanced ENaC abundance at the cell surface in HEK 293 cells. This resulted from altered endocytic sorting; USP8 abolished ENaC degradation in the endocytic pathway, but it had no effect on ENaC endocytosis. USP8 interacted with ENaC, as detected by co-immunoprecipitation, and it deubiquitinated ENaC. Consistent with a functional role for deubiquitination, mutation of the cytoplasmic lysines of ENaC reduced the effect of USP8 on ENaC cell surface abundance. In contrast to USP8, USP2-45 increased ENaC surface abundance by reducing endocytosis but not degradation. Thus, USP8 and USP2-45 selectively modulate ENaC trafficking at different steps in the endocytic pathway. Together with previous work, the data indicate that the ubiquitination state of ENaC is critical for the regulation of epithelial Na(+) absorption.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
This study identifies USP8 as a deubiquitinating enzyme that raises epithelial Na+ channel (ENaC) surface abundance and current by blocking ENaC degradation in the endocytic pathway, without affecting endocytosis. It further shows that USP2-45 acts at the opposite step, reducing ENaC endocytosis without altering degradation, indicating that DUBs selectively modulate distinct trafficking steps.
Key findings
- USP8 increased amiloride-sensitive ENaC current by almost 2-fold in Xenopus oocytes; the catalytically inactive USP8 mutant (C786S) did not alter current. USP8 also increased amiloride-sensitive short-circuit current in mpkCCD collecting duct monolayers.
- USP8 increased cell surface abundance of α-, β-, and γENaC in HEK 293 cells (selectively the proteolytically cleaved forms) without changing total ENaC in cell lysate.
- USP8 did not alter the rate of ENaC endocytosis, even when Nedd4-2 was coexpressed to accelerate it, but abolished degradation of biotinylated αENaC (control half-life ~70 min) and βENaC; it also reversed Nedd4-2-shortened βENaC half-life (<40 min).
- USP8 co-immunoprecipitated with α-, β-, and γENaC and reduced Nedd4-2-catalyzed mono- and polyubiquitination of all three subunits. Mutation of cytoplasmic lysines (α-, β-, γK-RENaC) significantly reduced, but did not abolish, the USP8 effect on surface abundance.
- In contrast, USP2-45 increased α-, β-, and γENaC surface abundance, slowed ENaC endocytosis, and did not alter α- or βENaC degradation.
Methods
- Electrophysiology: two-electrode voltage clamp at −60 mV in Xenopus laevis oocytes injected with human α-, β-, γENaC cDNA (0.2 ng each) ± USP8 or empty vector (0.6 ng), with 10 μM amiloride to define ENaC current; Ussing chamber short-circuit current in mpkCCDc14 collecting duct monolayers transfected with USP8 or empty plasmid (2.8 μg).
- HEK 293T cell assays: cell surface biotinylation with sulfo-NHS-biotin and NeutrAvidin isolation, densitometry (ImageJ); endocytosis measured by trypsin cleavage of αCl-2ENaC followed by 0–20 min incubation at 37 °C; degradation measured by pulse-biotinylating surface ENaC and chasing 0–120 min; co-immunoprecipitation and ubiquitin-HA immunoprecipitation with immunoblotting.
Limitations
- The paper states that the mechanism coordinating the opposing actions of Nedd4-2 and USP8 within the trafficking complex remains to be identified, and that it is not known whether USP8 and USP2-45 act via compartmentalization or by targeting different lysine subsets.
- The authors note the unexpected finding that lysine mutation did not fully abolish USP8's effect, raising the possibility of a second, deubiquitination-independent mechanism that requires further work.
- Evident from the text: mechanistic conclusions rest largely on overexpression in heterologous systems (oocytes, HEK 293T) and a mouse collecting duct line, with no in vivo animal or human data reported.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
1 of 30 cited sources checked · 1 supported · 0 flagged
- Findingown data§ Abstract
USP8 has no effect on ENaC endocytosis.
“USP8 abolished ENaC degradation in the endocytic pathway, but it had no effect on ENaC endocytosis.”
- Also stated in: § RESULTS · plain
“USP8 did not alter the rate of ENaC endocytosis (Fig. 3, A and B).”
Quote in the paperSubstantial claim - Also stated in: § RESULTS · plain
- Findingown data§ RESULTS
In the presence of Nedd4-2, ENaC endocytosis was very rapid, with the majority of ENaC removed from the cell surface by the 5-min time point.
“ENaC endocytosis was very rapid in the presence of Nedd4-2; the majority of ENaC was removed from the cell surface by the 5-min time point.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
ENaC current was not altered by a catalytically inactive USP8 mutant (C786S).
“In contrast, ENaC current was not altered by a catalytically inactive USP8 mutant (C786S).”
Quote in the paperSubstantial claim- Rests on an assumption: The USP8 mutant C786S is catalytically inactive.
- Findingown data§ RESULTS
USP8 increases ENaC current in collecting duct epithelia.
“Overexpression of USP8 in mpkCCD monolayers increased amiloride-sensitive short-circuit current (Fig. 1C).”
Quote in the paperSubstantial claim - Findingown data§ Abstract
Mutation of the cytoplasmic lysines of ENaC reduces the effect of USP8 on ENaC cell surface abundance.
“Consistent with a functional role for deubiquitination, mutation of the cytoplasmic lysines of ENaC reduced the effect of USP8 on ENaC cell surface abundance.”
Quote in the paperSubstantial claim
- Findingown data§ Abstract
USP8 deubiquitinates ENaC.
“USP8 interacted with ENaC, as detected by co-immunoprecipitation, and it deubiquitinated ENaC.”
Quote in the paperSubstantial claim - Findingown data§ Abstract
USP8 increases ENaC current in Xenopus oocytes.
“USP8 increased ENaC current in Xenopus oocytes and collecting duct epithelia”
- Also stated in: § RESULTS · plain
“We found that USP8 increased ENaC current by almost 2-fold.”
Quote in the paperSubstantial claim - Also stated in: § RESULTS · plain
- Findingown data§ Abstract
USP8 interacts with ENaC, as detected by co-immunoprecipitation.
“USP8 interacted with ENaC, as detected by co-immunoprecipitation, and it deubiquitinated ENaC.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
USP8 did not increase ENaC abundance in the total cell lysate.
“In contrast to its effects on ENaC cell surface abundance, USP8 did not increase ENaC abundance in the total cell lysate (Fig. 2A, middle panel), which principally reflects the fraction of ENaC in the biosynthetic pathway.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
USP8 did not alter the rate of ENaC endocytosis.
“USP8 did not alter the rate of ENaC endocytosis (Fig. 3, A and B).”
Quote in the paperSubstantial claim - Findingown data§ Abstract
USP8 abolishes ENaC degradation in the endocytic pathway.
“USP8 abolished ENaC degradation in the endocytic pathway, but it had no effect on ENaC endocytosis.”
Quote in the paperSubstantial claim - Findingown data§ Abstract
USP8 enhances ENaC abundance at the cell surface in HEK 293 cells.
“USP8 increased ENaC current in Xenopus oocytes and collecting duct epithelia and enhanced ENaC abundance at the cell surface in HEK 293 cells.”
- Also stated in: § RESULTS · plain
“We found that USP8 increased the abundance of α-, β-, and γENaC at the cell surface (Fig. 2A, upper panel; the data are quantitated in Fig. 2B).”
Quote in the paperSubstantial claim - Also stated in: § RESULTS · plain
- Findingown data§ RESULTS
USP8 reversed the effect of Nedd4-2, reducing αENaC ubiquitination.
“We found that USP8 reversed the effect of Nedd4-2, reducing αENaC ubiquitination (Fig. 6A; the data are quantitated in Fig. 6D).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
USP2-45 increased the cell surface abundance of β- and γENaC.
“USP2-45 also increased the cell surface abundance of β- and γENaC (Fig. 8, A and B).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
USP2-45 had no effect on αENaC in the total cell lysate.
“but had no effect on αENaC in the total cell lysate (Fig. 8A, lower panel).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
In HEK 293 cells expressing ENaC without USP8, biotinylated αENaC was degraded with a half-life of ∼70 min.
“In the absence of USP8, biotinylated αENaC was degraded with a half-life of ∼70 min (Fig. 4, A and B).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Nedd4-2 enhanced ubiquitination of β- and γENaC.
“Similar to αENaC, Nedd4-2 enhanced ubiquitination of β- and γENaC”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
USP8 coprecipitates with γENaC.
“and γENaC (Fig. 5C).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
USP8 prevented degradation of biotinylated βENaC.
“Similarly, USP8 also prevented degradation of biotinylated βENaC (Fig. 4, C and D).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
USP8 coprecipitates with βENaC.
“we detected coprecipitation between USP8 and βENaC (Fig. 5B)”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Nedd4-2 shortened the half-life of biotinylated βENaC to <40 min.
“This shortened the half-life of biotinylated βENaC to <40 min (Fig. 4, E and F).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
USP2-45 did not alter βENaC degradation.
“We found that USP2-45 did not alter βENaC degradation (Fig. 9, C and D).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
USP2-45 increased the quantity of αENaC at the cell surface.
“USP2-45 increased the quantity of αENaC at the cell surface (biotinylated fraction) (Fig. 8A, upper panel; the data are quantitated in Fig. 8B)”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Following trypsin cleavage, Nedd4-2 caused a rapid decrease in the pool of cleaved ENaC channels at the cell surface.
“Following trypsin cleavage, Nedd4-2 caused a rapid decrease in the pool of cleaved channels at the cell surface (Fig. 9, A and B).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
USP2-45 did not reduce αENaC degradation.
“Similarly, USP2-45 did not reduce αENaC degradation (Fig. 9, E and F).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
USP8 abolished degradation of biotinylated αENaC.
“We found that USP8 abolished degradation of biotinylated αENaC (Fig. 4, A and B).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
The rate of decrease of cleaved ENaC at the cell surface was much slower in cells coexpressing USP2-45.
“In contrast, the rate of decrease was much slower in cells coexpressing USP2-45 (Fig. 9, A and B).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
When αENaC was immunoprecipitated, USP8 was detected by immunoblotting only in cells coexpressing both proteins.
“When we immunoprecipitated αENaC, we detected coprecipitated USP8 by immunoblotting only in cells that coexpressed both proteins.”
Quote in the paperSubstantial claim - Premisecitation§ Abstract
The ubiquitination state of ENaC is also controlled by deubiquitinating enzymes (DUBs), which remove ubiquitin from ENaC subunits.
“The ubiquitination state of ENaC is also controlled by deubiquitinating enzymes (DUBs), which remove ubiquitin from ENaC subunits.”
Quote in the paperSubstantial claim - Premisecitation§ Abstract
Ubiquitination plays a key role in trafficking of the epithelial Na+ channel (ENaC).
“Ubiquitination plays a key role in trafficking of the epithelial Na+ channel (ENaC).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [5] Schild, 1995, A mutation in the epithelial sodium channel causing Liddle disease increases channel activity in the Xenopus laevis oocyte expression system, Proc. Natl. Acad. Sci. U.S.A. source
- cites [6] Snyder, 1995, Mechanism by which Liddle's syndrome mutations increase activity of a human epithelial Na+ channel, Cell source
- Premisecitation§ RESULTS
Nedd4-2 accelerates ENaC endocytosis by catalyzing ENaC ubiquitination.
“by catalyzing ENaC ubiquitination, Nedd4-2 accelerates ENaC endocytosis (17”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [17] Kabra, 2008, Nedd4-2 induces endocytosis and degradation of proteolytically cleaved epithelial Na+ channels, J. Biol. Chem. source
- Premisecitation§ Abstract
In the endosome, ubiquitinated ENaC is detected and sorted to lysosomes by Hrs.
“In the endosome, ubiquitinated ENaC is detected and sorted to lysosomes by Hrs (hepatocyte growth factor-regulated tyrosine kinase substrate).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationreasoning§ Abstract
The ubiquitination state of ENaC is critical for the regulation of epithelial Na+ absorption.
“Together with previous work, the data indicate that the ubiquitination state of ENaC is critical for the regulation of epithelial Na+ absorption.”
Quote in the paperSubstantial claim - Interpretationreasoning§ Abstract
USP8 and USP2-45 selectively modulate ENaC trafficking at different steps in the endocytic pathway.
“Thus, USP8 and USP2-45 selectively modulate ENaC trafficking at different steps in the endocytic pathway.”
Quote in the paperSubstantial claim - Premisenone given§ Abstract
Two DUBs that deubiquitinate ENaC have been identified.
“Two DUBs that deubiquitinate ENaC have been identified.”
Quote in the paperSubstantial claim - Interpretationown data§ RESULTS
ENaC lysines contribute to regulation by USP8.
“Thus, ENaC lysines contribute to regulation by USP8.”
Quote in the paperSubstantial claim - Interpretationreasoning§ DISCUSSION
USP8 appears to function at the early endosome sorting step for ENaC.
“In the case of ENaC, USP8 appears to function at this step.”
Quote in the paperSubstantial claim - Interpretationreasoning§ DISCUSSION
USP8 can play multiple roles in endosomal cargo sorting.
“Thus, USP8 can play multiple roles in endosomal cargo sorting.”
Quote in the paperSubstantial claim - Interpretationown data§ RESULTS
USP8 increases ENaC cell surface abundance by modulating a trafficking step other than endocytosis.
“Together, the data indicate that USP8 increases ENaC cell surface abundance by modulating a trafficking step other than endocytosis.”
Quote in the paperSubstantial claim - Premisecitation§ RESULTS
Cytoplasmic lysines in all three ENaC subunits are substrates for ubiquitination.
“which are substrates for ubiquitination (10”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationreasoning§ DISCUSSION
ENaC endocytic sorting is determined by the concerted actions of a complex of ubiquitin ligases, DUBs, and ubiquitin-interacting proteins that titrate the ENaC ubiquitination state and hence determine its fate.
“This suggests a model in which ENaC endocytic sorting is determined by the concerted actions of a complex of ubiquitin ligases, DUBs, and ubiquitin-interacting proteins, which titrate the ENaC ubiquitination state and hence determine its fate.”
Quote in the paperSubstantial claim - Interpretationown data§ RESULTS
USP8 interacts with ENaC.
“These results indicate that there is an interaction between USP8 and ENaC.”
Quote in the paperSubstantial claim - Interpretationown data§ RESULTS
USP2-45 reduces the rate of ENaC endocytosis.
“Thus, USP2-45 reduces the rate of ENaC endocytosis.”
Quote in the paperSubstantial claim - Interpretationreasoning§ DISCUSSION
This allows USP2-45 to selectively regulate endocytosis.
“This allows USP2-45 to selectively regulate endocytosis.”
Quote in the paperSubstantial claim - Interpretationown data§ DISCUSSION
There is selective control of ENaC endocytosis and degradation trafficking steps.
“This finding indicates there is selective control of these trafficking steps.”
Quote in the paperSubstantial claim - Interpretationown data§ RESULTS
USP8 can function as a DUB for all three ENaC subunits.
“These findings indicate that USP8 can function as a DUB for all three ENaC subunits.”
Quote in the paperSubstantial claim - Interpretationreasoning§ DISCUSSION
The endosomal sorting step is rate-limiting for ENaC degradation because it is much slower than ENaC endocytosis.
“The endosomal sorting step is rate-limiting for ENaC degradation because it is much slower than ENaC endocytosis.”
Quote in the paperNot a substantial claim - Interpretationreasoning§ DISCUSSION
USP8 can deubiquitinate cargo at multiple steps in the endocytic pathway.
“These seemingly incongruous findings can be explained by the observation that USP8 can deubiquitinate cargo at multiple steps in the endocytic pathway.”
Quote in the paperSubstantial claim - Interpretationreasoning§ DISCUSSION
The selective effects of USP2-45 and USP8 are likely based on compartmentalization.
“It seems likely that the selective effects of USP2-45 and USP8 are based on compartmentalization.”
Quote in the paperNot a substantial claim
- Probably not a substantial claim. 11
- It may state two separate claims as one. 22
- The quote only partly states this claim. 2
Probably not a substantial claim.
Premisecitation§ AbstractThe interaction between ENaC and Nedd4-2 is a critical convergence point for pathways that regulate Na+ absorption.
“The interaction between ENaC and Nedd4-2 is a critical convergence point for pathways that regulate Na+ absorption.”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [12] Debonneville, 2001, Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na+ channel cell surface expression, EMBO J. source
- cites [13] Snyder, 2004, cAMP and serum and glucocorticoid-inducible kinase (SGK) regulate the epithelial Na+ channel through convergent phosphorylation of Nedd4-2, J. Biol. Chem. source
- cites [14] Snyder, 2002, Serum and glucocorticoid-regulated kinase modulates Nedd4-2-mediated inhibition of the epithelial Na+ channel, J. Biol. Chem. source
It may state two separate claims as one.
Findingown data§ AbstractUSP2-45 increases ENaC surface abundance by reducing endocytosis but not degradation.
“In contrast to USP8, USP2-45 increased ENaC surface abundance by reducing endocytosis but not degradation.”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown data§ RESULTSUSP8 selectively increased surface expression of the cleaved forms of α- and γENaC.
“USP8 selectively increased surface expression of the cleaved forms.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ RESULTSUSP8 reversed the Nedd4-2 effect, abolishing degradation of biotinylated βENaC.
“USP8 reversed this effect, abolishing degradation of biotinylated βENaC (Fig. 4, E and F).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ RESULTSUSP8 increased surface expression of lysine mutant ENaC, but this increase was significantly less than its effect on wild-type ENaC.
“Although USP8 increased surface expression of the mutant channel, this increase was significantly less than the effect of USP8 on wild-type ENaC (Fig. 7, A and B).”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown data§ RESULTSUSP8 did not slow the rate of ENaC endocytosis when Nedd4-2 was coexpressed.
“However, USP8 did not slow the rate of ENaC endocytosis.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Findingreasoning§ RESULTSUSP2-45 was not detected in the biotinylated cell surface fraction.
“Because USP2-45 is a cytoplasmic protein, we did not detect it in the biotinylated fraction (supplemental Fig. S1).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown data§ RESULTSUSP8 reversed the Nedd4-2 effect, reducing ubiquitination of β- and γENaC.
“and USP8 reversed this effect, reducing ubiquitination (the data are quantitated in Fig. 6D).”
Quote in the paperSubstantial claimProbably not a substantial claim.
Premisecitation§ AbstractPrevious work indicated that ubiquitination enhances ENaC endocytosis and sorting to lysosomes for degradation.
“Previous work indicated that ubiquitination enhances ENaC endocytosis and sorting to lysosomes for degradation.”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation§ AbstractNedd4-2 reduces ENaC expression on the cell surface at two distinct sites in the endocytic pathway.
“Nedd4-2 reduces ENaC expression on the cell surface at two distinct sites in the endocytic pathway.”
Quote in the paperNot a substantial claim0 of 2 sources checkedIt may state two separate claims as one.
Interpretationown data§ RESULTSUSP8 selectively enhances ENaC at the cell surface without altering its total abundance, consistent with an alteration in ENaC trafficking.
“Thus, USP8 selectively enhances ENaC at the cell surface without altering its total abundance, consistent with an alteration in ENaC trafficking.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation§ AbstractA defect in ubiquitination causes Liddle syndrome, an inherited form of hypertension.
“Moreover, a defect in ubiquitination causes Liddle syndrome, an inherited form of hypertension.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [5] Schild, 1995, A mutation in the epithelial sodium channel causing Liddle disease increases channel activity in the Xenopus laevis oocyte expression system, Proc. Natl. Acad. Sci. U.S.A. source
- cites [6] Snyder, 1995, Mechanism by which Liddle's syndrome mutations increase activity of a human epithelial Na+ channel, Cell source
It may state two separate claims as one.
Premisecitation§ IntroductionNa+ absorption is regulated in part by the ubiquitination state of ENaC subunits, which in turn controls ENaC trafficking.
“Na+ absorption is regulated in part by the ubiquitination state of ENaC subunits, which in turn controls ENaC trafficking.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [5] Schild, 1995, A mutation in the epithelial sodium channel causing Liddle disease increases channel activity in the Xenopus laevis oocyte expression system, Proc. Natl. Acad. Sci. U.S.A. source
- cites [6] Snyder, 1995, Mechanism by which Liddle's syndrome mutations increase activity of a human epithelial Na+ channel, Cell source
It may state two separate claims as one.
Interpretationown data§ RESULTSUSP8 stimulates ENaC in both Xenopus oocytes and renal epithelia.
“Thus, USP8 stimulates ENaC in both Xenopus oocytes and renal epithelia.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationreasoning§ DISCUSSIONNedd4-2 catalyzes ENaC ubiquitination and reduces Na+ absorption by enhancing ENaC endocytosis and sorting ENaC to lysosomes for degradation, reducing recycling.
“The E3 ubiquitin ligase Nedd4-2 catalyzes ENaC ubiquitination and reduces Na+ absorption by altering ENaC trafficking at two distinct steps in the endocytic pathway; it enhances ENaC endocytosis, and it sorts ENaC to lysosomes for degradation, reducing ENaC recycling to the cell surface (Fig. 10).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Premisecitation§ RESULTSNedd4-2-mediated ubiquitination of ENaC promotes lysosomal degradation and reduces recycling.
“This endosomal sorting decision is governed in part by Nedd4-2-mediated ubiquitination of ENaC; ubiquitination promotes lysosomal degradation and reduces recycling (11”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation§ DISCUSSIONUSP8 overexpression reduces degradation of the EGF receptor.
“USP8 overexpression reduces degradation of the EGF receptor (36”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [36] Mizuno, 2005, Regulation of epidermal growth factor receptor down-regulation by UBPY-mediated deubiquitination at endosomes, Mol. Biol. Cell source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisecitation§ DISCUSSIONUSP8 deubiquitinates additional membrane proteins, with complex functional effects.
“USP8 has been shown to deubiquitinate additional membrane proteins, although the functional effects of deubiquitination are complex.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [36] Mizuno, 2005, Regulation of epidermal growth factor receptor down-regulation by UBPY-mediated deubiquitination at endosomes, Mol. Biol. Cell source
- cites [37] Balut, 2011, Role of ubiquitylation and USP8-dependent deubiquitylation in the endocytosis and lysosomal targeting of plasma membrane KCa3.1, FASEB J. source
- cites [38] Berlin, 2010, Regulation of epidermal growth factor receptor ubiquitination and trafficking by the USP8·STAM complex, J. Biol. Chem. source
It may state two separate claims as one.
Interpretationown data§ RESULTSUSP8 increases ENaC cell surface abundance by modulating endosomal sorting rather than by altering ENaC trafficking at the cell surface.
“Thus, USP8 increases ENaC cell surface abundance by modulating endosomal sorting rather than by altering ENaC trafficking at the cell surface.”
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.
Premisecitation§ RESULTSUSP2-45 reduces ENaC ubiquitination and increases ENaC abundance at the cell surface.
“Previous work indicated that USP2-45 reduces ENaC ubiquitination and increases ENaC abundance at the cell surface (21”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [21] Fakitsas, 2007, Early aldosterone-induced gene product regulates the epithelial sodium channel by deubiquitylation, J. Am. Soc. Nephrol. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation§ DISCUSSIONUSP8 overexpression reduces degradation of KCa3.1.
“and KCa3.1 (37”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [37] Balut, 2011, Role of ubiquitylation and USP8-dependent deubiquitylation in the endocytosis and lysosomal targeting of plasma membrane KCa3.1, FASEB J. source
It may state two separate claims as one.
Premisecitation§ RESULTSNedd4-2 catalyzes monoubiquitination and polyubiquitination of αENaC.
“Nedd4-2 catalyzed monoubiquitination and polyubiquitination of αENaC, as we reported previously (11”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Zhou, 2007, Nedd4-2 catalyzes ubiquitination and degradation of cell surface ENaC, J. Biol. Chem. source
It may state two separate claims as one.
Interpretationreasoning§ DISCUSSIONUSP8 and USP2-45 both increase ENaC cell surface abundance and ENaC current, but they do so at different locations within the endocytic pathway.
“Thus, USP8 and USP2-45 both increase ENaC cell surface abundance and ENaC current, but they do so at different locations within the endocytic pathway.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Premisecitation§ DISCUSSIONHrs detects ubiquitinated ENaC and directs it to the multivesicular body/lysosomal compartment for degradation.
“we found that Hrs, another component of ESCRT-0, detects ubiquitinated ENaC and directs it to the multivesicular body/lysosomal compartment for degradation (20”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [20] Zhou, 2010, Hrs controls sorting of the epithelial Na+ channel between endosomal degradation and recycling pathways, J. Biol. Chem. source
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
Interpretationnone given§ DISCUSSIONUSP2-45 functions at the endocytosis step, complementing USP8.
“This complements the activity of USP2-45, which functions at the endocytosis step.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisecitation§ DISCUSSIONUSP8 localizes to endosomes, where it interacts with STAM, a component of the ESCRT-0 complex.
“earlier work localizing USP8 to endosomes, where it interacts with STAM, a component of the ESCRT-0 complex (26”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [26] Kato, 2000, A deubiquitinating enzyme UBPY interacts with the Src homology 3 domain of Hrs-binding protein via a novel binding motif PX(V/I)(D/N)RXXKP, J. Biol. Chem. source
It may state two separate claims as one.
Interpretationreasoning§ DISCUSSIONBoth Nedd4-2-mediated endocytosis and lysosomal sorting reduce epithelial Na+ absorption.
“Both reduce epithelial Na+ absorption.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown data§ RESULTSUSP2-45 increases ENaC surface expression by reducing endocytosis but not by altering ENaC trafficking in endosomes.
“Together, the data indicate that USP2-45 increases ENaC surface expression by reducing endocytosis but not by altering ENaC trafficking in endosomes.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown data§ DISCUSSIONUSP8 has an important role in modulating the ubiquitination state of ENaC, functioning selectively at the endosomal sorting step of ENaC trafficking.
“In summary, USP8 has an important role in modulating the ubiquitination state of ENaC, functioning selectively at the endosomal sorting step of ENaC trafficking.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Premisecitation§ DISCUSSIONNedd4-2 interacts with Hrs and enhances the interaction between ENaC and Hrs by catalyzing ENaC ubiquitination.
“Nedd4-2 also interacts with Hrs and, by catalyzing ENaC ubiquitination, enhances the interaction between ENaC and Hrs (20”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [20] Zhou, 2010, Hrs controls sorting of the epithelial Na+ channel between endosomal degradation and recycling pathways, J. Biol. Chem. source
It may state two separate claims as one.
Interpretationown data§ RESULTSNedd4-2 regulates ENaC at both the endocytosis and degradation steps of endocytic trafficking, but USP8 selectively regulates ENaC degradation.
“It is intriguing that Nedd4-2 regulates ENaC at both the endocytosis and degradation steps of endocytic trafficking, but USP8 selectively regulates ENaC degradation.”
Quote in the paperSubstantial claim
The paper relies on this without support.
It is not known which trafficking steps are modulated by these DUBs and if additional DUBs play a role in ENaC trafficking.
“However, it is not known which trafficking steps are modulated by these DUBs and if additional DUBs play a role in ENaC trafficking.”
The paper relies on this without support.
The USP8 mutant C786S is catalytically inactive.
“In contrast, ENaC current was not altered by a catalytically inactive USP8 mutant (C786S).”
The paper relies on this without support.
The ubiquitination state of ENaC plays a key role in its trafficking in the endocytic pathway.
“The ubiquitination state of ENaC plays a key role in its trafficking in the endocytic pathway.”
The paper relies on this without support.
DUBs reduce ENaC ubiquitination and have the opposite effect on Na+ absorption.
“DUBs reduce ENaC ubiquitination and have the opposite effect on Na+ absorption.”
The paper relies on this without support.
USP8 functions as a ubiquitin peptidase, removing ubiquitin from cytoplasmic lysines.
“This was expected because USP8 functions as a ubiquitin peptidase, removing ubiquitin from cytoplasmic lysines.”
The paper relies on this without support.
In early endosomes, ubiquitination sorts cargo between recycling and degradation pathways; deubiquitination at this step can rescue cargo from degradation and increase recycling to the cell surface.
“In early endosomes, ubiquitination sorts cargo between recycling and degradation pathways. Deubiquitination at this step can rescue cargo from degradation and increase recycling to the cell surface.”
The paper relies on this without support.
Later in the trafficking pathway, after cargo is committed to the multivesicular bodies for degradation, ubiquitin is removed prior to delivery to intraluminal vesicles and lysosomal fusion; reducing deubiquitination at this step can decrease cargo degradation.
“Later in the trafficking pathway, after cargo is committed to the multivesicular bodies for degradation, ubiquitin is removed prior to delivery to intraluminal vesicles and lysosomal fusion. Reducing deubiquitination at this step can decrease cargo degradation.”
The paper relies on this without support.
The balance between ubiquitination and deubiquitination is critical in the regulation of epithelial Na+ absorption.
“The balance between ubiquitination and deubiquitination is critical in the regulation of epithelial Na+ absorption.”
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Metadata
- Authors
- Zhou, R., Tomkovicz, V. R., Butler, P. L., Ochoa, L. A., Peterson, Z. J., & Snyder, P. M.
- Affiliations
- University of Iowa (US)
- Corresponding author
- Snyder, Peter M.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2013-02
- Volume
- 288
- Issue
- 8
- Pages
- 5389-5397
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3581384
- OpenAlex
- W1978028274
- Semantic Scholar
- 369fdf51da47c59c60c5f96628c9458ded438fdd
- Cited by
- 47
- References
- 43
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 4 · 2022: 5 · 2021: 2 · 2020: 9 · 2019: 3 · 2018: 1 · 2017: 3 · 2016: 5 · 2015: 4 · 2014: 6 · 2013: 1
- FWCI
- 1.76
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Institut National de la Santé et de la Recherche Médicale
- National Heart, Lung, and Blood Institute (R29HL058812, HL-058812, R01HL058812, R01HL072256)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- USP8, epithelial Na+ channel, epithelial sodium channel, deubiquitination, ubiquitination, endosomal trafficking, endocytosis, lysosomal degradation, Liddle syndrome, sodium uptake, collecting duct epithelium
- MeSH terms
- Amiloride, Animals, Cell Membrane, Electrophysiology, Endocytosis, Gene Expression Regulation, Humans, Hypertension, Models, Biological, Oocytes, Endopeptidases, Endosomes, Xenopus, DNA, Complementary, Biotinylation, Protein Transport, Ubiquitin, Ubiquitin Thiolesterase, Epithelial Sodium Channels, Endosomal Sorting Complexes Required for Transport, HEK293 Cells
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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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