Affinage

UCHL5

Ubiquitin carboxyl-terminal hydrolase isozyme L5 · UniProt Q9Y5K5

Length
329 aa
Mass
37.6 kDa
Annotated
2026-06-10
72 papers in source corpus 35 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

UCHL5/UCH37 is a UCH-family deubiquitinating enzyme whose central function is to process Lys48-linked polyubiquitin at the 26S proteasome, where it acts exo-specifically from the distal end of the chain to support substrate degradation (PMID:16906146). The enzyme is intrinsically autoinhibited: its C-terminal extension drives homodimerization that occludes the ubiquitin-binding site of each catalytic domain, and this oligomeric state is disrupted by the C-terminal (DEUBAD) domain of hRpn13/ADRM1, which sequesters UCH37 into an active 1:1 complex and accelerates ubiquitin hydrolysis (PMID:24752541, PMID:25702870). hRpn13 docks UCH37 onto the proteasome by binding the base subunit Rpn2, and this interaction is required for both UCH37 activity and its protein stability in cells (PMID:16990800, PMID:17139257, PMID:32631902). Crystallographic and biophysical work established that the UCH37 C-terminal ULD domain engages both regulatory partners at a shared interface, with hRpn13 stabilizing a ubiquitin-competent conformation while INO80G/NFRKB of the nuclear hINO80 chromatin-remodeling complex instead inhibits UCH37 by molecular mimicry of ubiquitin, locking the enzyme inactive until transient proteasome–INO80 contact relieves the block (PMID:25702870, PMID:25702872, PMID:18922472). Beyond canonical exo-cleavage, UCH37 is a debranching deubiquitinase that selectively cleaves K48-branched chain architectures via a cryptic chain-binding site distal to the catalytic S1 site, an activity enhanced by RPN13 and required for efficient degradation of branched-chain-modified substrates and for proteasome recycling (PMID:33156996, PMID:34761751, PMID:35451368). UCH37 activity is non-redundant with other proteasomal DUBs, acting on a substrate-selective ubiquitinome (PMID:31703099, PMID:32631902), and its loss perturbs cell-cycle progression (PMID:26907685). Outside the proteasome, UCH37 deubiquitinates and stabilizes diverse substrates to tune signaling pathways: the TGF-β type I receptor ALK5 (PMID:16027725, PMID:37406898), Smoothened in Hedgehog signaling (PMID:28992318), and NLRP3 to promote inflammasome activation (PMID:36778113), and it removes K63-linked chains from E2F1 to activate transcription of pro-apoptotic target genes after DNA damage (PMID:26396186). UCH37 also acts in Wnt signaling through a catalytically independent scaffolding role that stabilizes and polymerizes Axin1 (PMID:35256667). UCH37 deletion in mice causes prenatal lethality with severe defects in embryonic brain development, establishing an essential developmental role (PMID:21048919).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 2001 Medium

    Before its proteasomal mechanism was understood, the question was which partners engage UCH37; an early screen mapped its C-terminal extension to a 19S subunit and a novel interactor, foreshadowing partner-dependent regulation.

    Evidence Yeast two-hybrid, in vitro binding and Co-IP identifying S14 and UIP1 binding the C-terminal extension

    PMID:11163772

    Open questions at the time
    • UIP1 functional significance never integrated into later mechanistic models
    • predates discovery of hRpn13 as the relevant proteasomal recruiter
  2. 2004 Medium

    Establishing physiological relevance, the fission yeast ortholog was shown to be the major proteasome-associated DUB, but dispensable for viability, revealing functional redundancy with other DUBs.

    Evidence Gene disruption and proteasome DUB activity assays in S. pombe

    PMID:15533439

    Open questions at the time
    • redundancy in yeast does not predict the essential mammalian role
    • did not identify which DUBs compensate
  3. 2005 Medium

    The first non-proteasomal substrate connection was made, linking UCH37 to TGF-β signaling by deubiquitinating and stabilizing the ALK5 receptor.

    Evidence GST pull-down, Co-IP, RNAi and luciferase reporter assays with Smad7 and ALK5

    PMID:16027725

    Open questions at the time
    • chain linkage on ALK5 not defined
    • direct vs scaffold-mediated deubiquitination not separated
  4. 2006 High

    The core proteasomal mechanism was resolved: UCH37 provides the 19S exo-specific K48 isopeptidase activity and is recruited and de-repressed by hRpn13/ADRM1, which docks the enzyme onto Rpn2.

    Evidence Three concurrent studies using biochemical fractionation, reconstitution, Ub-AMC activity assays, Co-IP and knockdown

    PMID:16906146 PMID:16990800 PMID:17139257

    Open questions at the time
    • structural basis of autoinhibition relief not yet defined
    • branched-chain specificity not yet appreciated
  5. 2008 High

    UCH37 regulation was shown to be bidirectional: the nuclear hINO80 complex holds it inactive, while proteasome interaction activates it, defining context-dependent control through partner complexes.

    Evidence Mass spectrometry, Co-IP and in vitro DUB activity assays defining dual complex membership

    PMID:18922472

    Open questions at the time
    • physiological role of UCH37 within hINO80 chromatin remodeling not defined
    • in vivo trigger of proteasome–INO80 contact unknown
  6. 2011 Medium

    Early structural work on full-length and catalytic-domain constructs visualized the elongated C-terminal extension and an inactive active-site configuration, setting up the conformational-activation model.

    Evidence X-ray crystallography of full-length and truncated UCH37 constructs

    PMID:19836345 PMID:21953935 PMID:21995438

    Open questions at the time
    • apo structures lacked partner or ubiquitin context
    • activation transitions inferred rather than captured
  7. 2014 High

    The autoinhibition mechanism was solved biophysically: the C-terminal extension mediates oligomerization that blocks the ubiquitin site, and Rpn13C disrupts this to give ~12-fold activation.

    Evidence NMR, SAXS, FRET, mutagenesis and Ub-AMC activity assays

    PMID:24752541

    Open questions at the time
    • dynamics within the intact proteasome not addressed
  8. 2015 High

    Crystal structures with RPN13 and NFRKB DEUBAD domains explained opposing regulation: both bind the ULD domain but RPN13 disrupts dimerization to activate while NFRKB blocks the ubiquitin site by molecular mimicry.

    Evidence X-ray crystallography of UCH37–RPN13 and UCH37–NFRKB complexes with biochemical and mutagenesis validation

    PMID:25702870 PMID:25702872

    Open questions at the time
    • does not address branched-chain selectivity
    • transition between inactive and active states in cells not resolved
  9. 2013 High

    A structure with ubiquitin (UbVME) explained exo-specificity: the ULD domain stabilizes a K48-E51 salt bridge unique to the distal ubiquitin of a K48 chain.

    Evidence X-ray crystallography of Trichinella UCH37–UbVME and mutagenesis

    PMID:23617878

    Open questions at the time
    • ortholog structure; human-specific contacts not directly shown
  10. 2015 Medium

    UCH37 was shown to act in transcription by removing K63 (not K48) chains from E2F1 without affecting stability, activating E2F1 pro-apoptotic targets in a feedback loop after DNA damage.

    Evidence Co-IP, ubiquitination assays, catalytic-dead mutant, ChIP and reporter assays

    PMID:26396186

    Open questions at the time
    • whether this occurs via hINO80 chromatin association not tested
    • direct vs indirect E2F1 engagement at promoters unclear
  11. 2016 Medium

    UCH37 and hRpn13 were linked to cell-cycle control, with knockdown causing G0/G1 stalling and hRpn13 loss reducing UCH37 levels.

    Evidence siRNA knockdown, FACS cell-cycle analysis, protein quantification

    PMID:26907685

    Open questions at the time
    • substrates driving the arrest not identified
  12. 2017 High

    Structural work on the hRpn13–hRpn2 interface and the inhibitor RA190 clarified proteasome docking and showed RA190 directly inactivates UCH37 as well as hRpn13.

    Evidence X-ray crystallography, ITC, NMR, cell-based assays with hRpn13 deletion

    PMID:28598414

    Open questions at the time
    • RA190 binding site on UCH37 itself not structurally defined
  13. 2020 High

    A redefinition of catalytic role: UCH37 is a debranching DUB that selectively cleaves K48-branched chains, an activity enhanced by RPN13 and required for degradation of branched-chain substrates.

    Evidence Defined synthetic/enzymatic chain substrates, intact MS, reconstituted proteasomes, pulse-chase proteomics

    PMID:33156996 PMID:34761751

    Open questions at the time
    • fraction of cellular substrates that are branched not quantified
  14. 2022 High

    The structural basis of debranching was localized to a cryptic K48-chain binding site opposite the canonical S1 site, required for debranching and branched-substrate degradation.

    Evidence HDX-MS, crosslinking, SAXS, NMR, docking, mutagenesis and quantitative proteomics

    PMID:35451368

    Open questions at the time
    • how this site is regulated within the assembled proteasome not resolved
  15. 2019 Medium

    Cell-based genetics confirmed UCH37 maintains proteasomal Rpn13 and acts on selective substrates such as β-catenin, linking it to Wnt-related turnover and proliferation control.

    Evidence CRISPR/Cas9 knockout, immunoblotting, ubiquitination and proliferation/motility assays

    PMID:30726867

    Open questions at the time
    • direct vs indirect β-catenin deubiquitination not separated
  16. 2020 Medium

    Inactive-mutant and knockout studies established that UCH37's substrate set is non-redundant and distinct from USP14, and that hRpn13 stabilizes UCH37 specifically through binding rather than proteasome docking.

    Evidence Catalytic-dead overexpression, ubiquitin-IP MS, CRISPR editing and proteasome fractionation

    PMID:31703099 PMID:32631902

    Open questions at the time
    • full substrate inventory not defined
    • rules selecting UCH37 vs USP14 substrates unknown
  17. 2022 Medium

    A catalysis-independent function was uncovered: UCH37 binds multiple Axin1 domains and promotes Axin1 stabilization and polymerization, acting as a scaffold in Wnt regulation upstream of β-catenin.

    Evidence Co-IP, domain mapping, catalytic-dead mutant and Wnt reporter assays

    PMID:35256667

    Open questions at the time
    • mechanism of polymerization promotion unclear
    • relationship to its enzymatic β-catenin effects not reconciled
  18. 2018 Medium

    UCH37 was shown to regulate Hedgehog signaling by deubiquitinating and stabilizing Smoothened, an effect enhanced by RPN13.

    Evidence Co-IP, ubiquitination assays, genetic epistasis in Drosophila and mammalian cells

    PMID:28992318

    Open questions at the time
    • chain linkage on Smo not defined
    • whether proteasome-associated or free UCH37 acts not resolved
  19. 2024 Medium

    A series of disease-context studies established UCH37 as a recurrent NLRP3 deubiquitinase that stabilizes NLRP3 and promotes inflammasome activation across hepatocytes, mesenchymal stem cells, and vascular smooth muscle.

    Evidence Co-IP, ubiquitination assays, siRNA/inhibitor, m6A regulation (RIP/luciferase) and in vivo models

    PMID:34431717 PMID:36778113 PMID:37044315

    Open questions at the time
    • direct interaction not uniformly demonstrated
    • K63 vs stability mechanisms reported inconsistently across contexts
  20. 2025 Medium

    Additional substrate links broadened UCH37's signaling reach, stabilizing PKCα with USP14 to drive NF-κB activation, stabilizing ELK3 in pancreatic cancer, ALK5 in chondrocytes, and ZRANB1 to modulate ferroptosis, while also influencing autophagic flux.

    Evidence Co-IP, ubiquitination assays, knockdown/knockout, CHX-chase, autophagy flux and xenograft/in vivo models

    PMID:36328194 PMID:37406898 PMID:39912491 PMID:40804247 PMID:42037453

    Open questions at the time
    • several rest on single-lab Co-IP without reciprocal validation
    • direct vs proteasome-indirect mechanisms not separated
  21. 2010 Medium

    Genetic evidence established UCH37's essentiality in mammals, with knockout causing prenatal lethality and severe brain developmental defects.

    Evidence Conditional knockout mouse model with histological analysis

    PMID:21048919

    Open questions at the time
    • molecular pathway underlying the brain phenotype not identified
    • which UCH37 substrates drive lethality unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How UCH37's many cytoplasmic/nuclear signaling substrates relate to its proteasome- and INO80-bound pools, and which engagements are direct catalytic versus scaffolding or proteasome-indirect, remains unresolved.
  • substrate-targeting rules for free vs complex-bound UCH37 undefined
  • chain linkages cleaved on many substrates not directly determined
  • no unifying model connecting developmental essentiality to specific substrate pathways

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0140098 catalytic activity, acting on RNA 4 GO:0003723 RNA binding 3 GO:0016787 hydrolase activity 3 GO:0060090 molecular adaptor activity 1
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-1640170 Cell Cycle 1 R-HSA-74160 Gene expression (Transcription) 1 R-HSA-9612973 Autophagy 1
Partners
ADRM1AXIN1NFRKBNLRP3RPN2SMAD7USP14ZRANB1
Complex memberships
26S proteasome (19S/PA700 regulatory particle)hINO80 chromatin-remodeling complex

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 UCHL5/Uch37 is responsible for the ubiquitin isopeptidase activity in the PA700 (19S) proteasome regulatory complex, specifically disassembling Lys48-linked polyubiquitin from the distal end of the chain (exo-specific activity). It is recruited to the proteasome via Adrm1 (hRpn13), which binds through proteasomal subunit S1/Rpn2. Adrm1 binds the C-terminal tail of Uch37 and relieves Uch37 autoinhibition, accelerating ubiquitin-AMC hydrolysis. Incorporation into the full 19S complex is required for efficient polyubiquitin chain processing. Biochemical fractionation, in vitro DUB activity assays (ubiquitin-AMC), mass spectrometry, Co-IP, identification of Adrm1 as hRpn13 ortholog Nature cell biology High 16906146
2006 hRpn13 (ADRM1) recruits UCH37 to 26S proteasomes via physical interaction between the KEKE-motif-containing C-terminal regions of both proteins; hRpn13 interacts with the base subunit Rpn2 via its N-terminus. Knockdown of hRpn13 causes loss of UCH37 protein levels and decreases deubiquitinating activity of 26S proteasomes, indicating hRpn13 is essential for UCH37 activity at the proteasome. Co-IP, siRNA knockdown, DUB activity assay, yeast-two-hybrid, domain mapping The EMBO journal High 16990800
2006 The C-terminal half of hRpn13 directly binds UCH37 and enhances its isopeptidase activity. Knockdown of hRpn13 in 293T cells increases cellular ubiquitin conjugates and decreases degradation of short-lived proteins. Overproduction of hRpn13 or its C-terminal half also impairs proteolysis and the latter induces cell death, acting as a dominant-negative. Affinity purification, Co-IP, siRNA knockdown, pulse-chase degradation assay, overexpression studies The EMBO journal High 17139257
2008 In addition to its proteasomal role, Uch37 is associated with the human Ino80 chromatin-remodeling complex (hINO80) in the nucleus where it is held in an inactive state. Uch37 can be activated by transient interaction of the Ino80 complex with the proteasome. Thus, Uch37 activity is modulated both positively (by proteasomal binding) and negatively (by hINO80 binding) via dynamic interactions with partner proteins. Mass spectrometry, Co-IP, in vitro DUB activity assays (ubiquitin-AMC) Molecular cell High 18922472
2005 UCH37 interacts with Smad7 (and weakly with Smad2/Smad3) via a region distinct from the Smad7 PY-motif. Endogenous Smad7 and UCH37 form a stable complex. UCH37 can deubiquitinate and stabilize the type I TGF-β receptor (ALK5). Overexpression of UCH37 upregulates TGF-β-dependent transcription; RNAi-mediated knockdown reverses this effect. GST pull-down, Co-IP, overexpression, RNAi knockdown, luciferase reporter assay Oncogene Medium 16027725
2015 Crystal structures of UCH37 in complex with RPN13 (DEUBAD domain) and NFRKB (INO80G DEUBAD domain) reveal that: RPN13 activates UCH37 by disrupting dimerization and stabilizing a surface competent for ubiquitin binding while modulating the active-site crossover loop; NFRKB/INO80G inhibits UCH37 by blocking the ubiquitin-binding site and disrupting the enzyme active site through molecular mimicry of ubiquitin. Both make similar contacts to the UCH37 C-terminal domain but different contacts to the catalytic UCH domain. X-ray crystallography, biochemical DUB activity assays, mutagenesis Molecular cell High 25702870
2015 Crystal structures of UCH37 complexed with RPN13 and NFRKB confirm that RPN13 activates UCH37 partly by disrupting homodimerization and by stabilizing a ubiquitin-binding competent conformation; NFRKB inhibits UCH37 by blocking the ubiquitin-binding site and disrupting the active site. The UCH37 C-terminal ULD domain contacts both regulatory partners at a shared interface. X-ray crystallography, biochemical activity assays Molecular cell High 25702872
2014 Uch37 oligomerizes (autoinhibits) in solution through interactions between its C-terminal extension (Hb, Hc, KEKE motifs) that block the ubiquitin-binding site of each catalytic domain in the homodimer. Rpn13C (C-terminal domain of Rpn13) disrupts Uch37 oligomerization by sequestering Uch37 into a 1:1 complex, activating it ~12-fold by rendering the active site accessible to ubiquitin. NMR, SAXS, FRET, mutagenesis, biochemical activity assay (Ub-AMC) Protein & cell High 24752541
2013 Crystal structures of UCH37 from Trichinella spiralis in complex with ubiquitin vinyl methyl ester (UbVME) show that the UCH37-like domain (ULD) makes direct contact with ubiquitin, stabilizing an unusual K48-E51 intramolecular salt bridge in ubiquitin that is favored only in the distal ubiquitin of a K48-linked chain, providing a structural explanation for UCH37's exo-specific deubiquitination. X-ray crystallography (UCH37-UbVME complex), mutagenesis Biochemistry High 23617878
2011 Crystal structure of full-length human Uch37 at 2.95 Å reveals an elongated, predominantly helical C-terminal extension with coiled-coil interactions. The catalytic domain is similar to other UCH enzymes. The structure provides the first complete view of the full-length human enzyme. X-ray crystallography Proteins Medium 21953935
2011 Crystal structures of the UCH37 catalytic domain show the catalytic cysteine in an unproductive orientation, representing an inactive (apo) form of the enzyme. This suggests structural transitions are required for activation, and that the crossover loop plays a role in activity regulation. X-ray crystallography (two truncated catalytic domain constructs) The FEBS journal Medium 21995438
2009 Crystal structure of the UCH37 catalytic domain reveals that helix-3 is collapsed (compared to UCH-L1 and UCH-L3), widening the substrate-binding P'-site and enabling UCH37 to accommodate larger adducts such as ubiquitin. X-ray crystallography, structural comparison Biochemical and biophysical research communications Medium 19836345
2020 UCH37/UCHL5 is a debranching deubiquitinase: it selectively cleaves K48-branched ubiquitin chain architectures, and this activity is markedly enhanced by proteasomal Ub receptor RPN13/ADRM1. Using reconstituted proteasome complexes, chain debranching by UCH37 promotes degradation of substrates modified with branched chains. Loss of UCH37 activity in proteome-wide pulse-chase experiments impairs global protein turnover. Synthetic and enzyme-derived ubiquitin chain substrates, intact mass spectrometry, reconstituted proteasome complexes, pulse-chase proteomics Molecular cell High 33156996
2021 UCH37 debranching specificity arises from contacts with the hydrophobic patches of both distal ubiquitins emanating from a branched node. RPN13 further enhances branched-chain specificity by restricting linear Ub chains from accessing the UCH37 active site. Catalytically inactive UCH37(C88A) at the proteasome causes aberrant retention of polyubiquitinated species and the RAD23B substrate shuttle factor, suggesting defects in proteasome recycling. NMR structural analysis, biochemical assays with defined ubiquitin chain substrates, cell-based experiments with catalytically inactive mutant eLife High 34761751
2022 A cryptic K48 ubiquitin chain-specific binding site exists on the opposite face of UCH37 from the canonical S1 ubiquitin-binding site. This site is required for chain debranching and proteasome-mediated degradation of proteins modified with branched chains. Targeted mutagenesis of this site impairs UCH37 debranching activity, and quantitative proteomics identifies specific substrates dependent on this site. Hydrogen-deuterium exchange mass spectrometry, chemical crosslinking, SAXS, NMR, molecular docking, mutagenesis, biochemical assays, quantitative proteomics eLife High 35451368
2004 In fission yeast, Uch2/Uch37 is the major deubiquitinating enzyme associated with the 26S proteasome. Disruption of the Uch2 gene is viable without obvious impairment of ubiquitin-dependent proteolysis, indicating redundancy with other DUBs. Gene disruption, DUB activity assay of proteasome fractions, genetic analysis Journal of molecular biology Medium 15533439
2010 UCH37 deletion in mice results in prenatal lethality associated with severe defects in embryonic brain development, demonstrating an essential role for Uch37 in mammalian development. Conditional knockout mouse model, histological analysis PloS one Medium 21048919
2001 UCH37 interacts via its C-terminal extension with S14 (a PA700/19S subunit) and with UIP1 (a novel UCH37-interacting protein). UIP1 competitively blocks the UCH37–S14 interaction in vitro. Yeast two-hybrid screen, in vitro binding assay, Co-IP, domain mapping FEBS letters Medium 11163772
2015 UCH37 deubiquitinates Lys63-linked (but not Lys48-linked) ubiquitin chains on E2F1, without affecting E2F1 protein stability. This deubiquitination activates E2F1 transcriptional activity. UCH37 is induced by E2F1 and rises during G1/S transition, forming a positive feedback loop. UCH37 localizes to promoters of E2F1 pro-apoptotic target genes (caspase 3, caspase 7, PARP1, Apaf-1) and activates them after DNA damage. Co-IP, ubiquitination assays, catalytically dead mutant, siRNA knockdown, ChIP, luciferase reporter The Journal of biological chemistry Medium 26396186
2016 hRpn13 and Uch37 are required for proper cell cycle progression; their knockdown causes stalling at G0/G1. Loss of hRpn13 correlates with a small but significant reduction in Uch37 protein levels, suggesting hRpn13 interaction stabilizes Uch37 in human cells. siRNA knockdown, FACS cell cycle analysis, protein level quantification The Journal of biological chemistry Medium 26907685
2018 UCHL5/UCH37 interacts with and deubiquitinates Smoothened (Smo), increasing its stability and promoting its accumulation at the cell membrane. Hedgehog (Hh) signaling enhances the UCHL5–Smo interaction. RPN13, an activator of UCHL5, enhances UCHL5's effect on Smo protein levels. UCH37 regulates mammalian Hh signaling by modulating hSmo ubiquitination and stability. Co-IP, ubiquitination assay, genetic epistasis (Drosophila and mammalian), overexpression/knockdown Journal of molecular cell biology Medium 28992318
2017 Structure of hRpn13 bound to a segment of hRpn2 reveals how hRpn13 docks into the proteasome; a proline-rich C-terminal hRpn2 extension stretches across the ubiquitin-binding (Pru) domain canyon of hRpn13, blocking an RA190-binding surface. RA190 directly binds and inactivates Uch37 (in addition to hRpn13), and hRpn13-deleted cells show abrogated RA190-induced substrate accumulation at proteasomes. X-ray crystallography, biophysical binding analysis (ITC, NMR), cell-based assays, hRpn13 deletion Nature communications High 28598414
2019 UCH37 deletion via CRISPR/Cas9 in mammalian cells decreases levels of proteasomal Rpn13, increases ubiquitinated β-catenin, and accelerates hydrogen peroxide-stimulated β-catenin degradation. UCH37 appears to maintain Rpn13 in the proteasome and to reverse ubiquitination of specific substrates including β-catenin, inhibiting cell proliferation and motility when deleted. CRISPR/Cas9 knockout, immunoblotting, ubiquitination assay, cell proliferation and motility assays Acta biochimica et biophysica Sinica Medium 30726867
2020 Inactive UCH37 mutant C88A causes accumulation of ubiquitinated proteins in HEK293T cells that are largely distinct from those accumulated by inactive USP14 (C114A), demonstrating non-redundant and substrate-selective roles for each proteasomal DUB. UCHL5 C88A also inhibits its own deubiquitination. Catalytically inactive mutant overexpression, ubiquitin immunoprecipitation, mass spectrometry, immunoblotting PloS one Medium 31703099
2020 Deletion of UCHL5 from HCT116 cells causes increased ubiquitinated protein levels in whole-cell extract and at proteasomes, showing UCHL5 activity cannot be fully compensated by other DUBs (including the two other proteasomal DUBs). Loss of full-length hRpn13 reduces UCHL5 levels, but cells expressing truncated hRpn13 (competent for UCHL5 binding but defective for proteasome interaction) maintain normal UCHL5 levels. CRISPR/Cas9 gene editing, immunoblotting, proteasome fractionation Molecular and cellular biology Medium 32631902
2021 UCHL5 deubiquitinates NLRP3 (removing K63-linked ubiquitin chains) to promote NLRP3 inflammasome assembly and activation in HCV-infected hepatocytes. siRNA knockdown of UCHL5 or DUB inhibitors abrogated NLRP3 inflammasome assembly, reduced IL-1β maturation, and decreased HCV replication. siRNA knockdown, DUB chemical inhibitors, ubiquitination assay, NLRP3 inflammasome activation assay, IL-1β ELISA Microbiology spectrum Medium 34431717
2022 UCHL5 physically interacts with multiple domains of Axin1 protein (a scaffolder of the β-catenin destruction complex) and is required for both Axin1 stabilization and Axin1 polymerization. This deubiquitination occurs at the DIX domain of Axin1 but does not require UCH L5's catalytic activity, establishing a non-enzymatic scaffolding role for UCHL5 in Wnt signaling regulation upstream of β-catenin. Co-IP, domain mapping, functional assays (Wnt reporter), catalytically dead mutant analysis Scientific reports Medium 35256667
2022 UCH37 directly deubiquitinates and stabilizes ELK3 protein in pancreatic adenocarcinoma cells. UCH37 relies on accumulated ELK3 to drive cell growth, stem-like properties, and migration. ELK3 activates Notch1 signaling as a downstream effector. Co-IP, ubiquitination assay, overexpression/knockdown, rescue experiment with ELK3 Experimental cell research Low 36328194
2023 ADRM1 upregulates UCH37 expression and binds UCH37 to activate its deubiquitinating activity; activated UCH37 in turn deubiquitinates and stabilizes ALK5 (TGF-β type I receptor), thereby maintaining extracellular matrix homeostasis in chondrocytes. Co-IP, ubiquitination assay, overexpression/knockout in vitro and in vivo (DMM mouse model), ADRM1 inhibitor RA190 International journal of biological macromolecules Medium 37406898
2023 UCHL5 deubiquitinates NLRP3 to enhance its protein stability, promoting NLRP3 inflammasome activation. NLRP3 directly binds UCHL5 and maintains UCHL5 stability through reducing ubiquitin-proteasome pathway degradation in mandibular mesenchymal stem cells. UCHL5 inhibition promotes NLRP3 ubiquitination and degradation, enhancing osteoblast differentiation. Co-IP, ubiquitination analysis, UCHL5 inhibitor (b-AP15), osteoblast differentiation assay, in vivo mandibular defect model International journal of biological sciences Medium 36778113
2024 UCHL5 modified by METTL14/YTHDF1-mediated m6A upregulation deubiquitinates NLRP3, enhancing its protein stability and promoting NLRP3 inflammasome activation in vascular smooth muscle cells, contributing to atherosclerosis progression. RIP assay, dual-luciferase reporter, Co-IP, ubiquitination analysis, siRNA knockdown, in vivo AS mouse model Experimental cell research Medium 37044315
2025 USP14 and UCHL5 synergistically stabilize PKCα by removing K48-linked ubiquitination chains from PKCα, thereby facilitating nuclear translocation of NF-κB and activating pro-oncogenic genes (C-MYC, BCL-XL) in anaplastic thyroid cancer cells. Co-IP, ubiquitination assay, siRNA knockdown, nuclear fractionation, xenograft model Cell death & disease Medium 40804247
2025 Downregulation of UCHL5 by siRNA reduces autophagy in HeLa cells by partially blocking autophagosome–lysosome fusion, linking proteasomal DUB activity to autophagic flux. In C. elegans, ubh-4/UCHL5 RNAi affects autophagosome and autolysosome numbers in a tissue-dependent manner without blocking lysosomal fusion. siRNA knockdown, autophagy flux assay (autophagosome/autolysosome quantification), C. elegans RNAi Biology open Medium 39912491
2024 UCHL5 directly interacts with ZRANB1 (via Co-IP) and stabilizes ZRANB1 protein by deubiquitination, extending its half-life by over 2-fold. UCHL5 overexpression enhances ferroptosis sensitivity while UCHL5 knockout protects against ferroptosis, with UCHL5 upregulating ZRANB1 and downregulating SLC7A11/GPX4. Co-IP, ubiquitination analysis, protein half-life assay (CHX chase), CRISPR/Cas9 knockout, ferroptosis assays (BODIPY C11, GSH, Fe2+), xenograft model Cancer biology & therapy Medium 42037453
2025 UCHL5 counteracts PROTAC-mediated degradation of AURKA in a manner dependent on ubiquitin ligase adaptor CRBN (but not VHL). UCHL5 acts broadly on CRBN-dependent PROTAC substrates, not specifically on AURKA, in contrast to OTUD6A which is AURKA-specific. siRNA screen (97 DUBs), orthogonal dTAG PROTACs, immunoblotting bioRxivpreprint Low
2015 UCH37 knockdown significantly inhibits TGF-β-dependent gene reporter activity and selectively decreases levels of TGF-β target genes (p21, PAI-1) during the early phase of TGF-β receptor activation. UCH37 knockdown in Colo-357 cells impairs cell migration without affecting TGF-β-dependent proliferation or EMT. Stable/inducible knockdown cell lines, luciferase reporter, RT-PCR, cell migration assay (wound-healing/transwell) The international journal of biochemistry & cell biology Medium 21187158

Source papers

Stage 0 corpus · 72 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Proteasome recruitment and activation of the Uch37 deubiquitinating enzyme by Adrm1. Nature cell biology 293 16906146
2013 A novel small molecule inhibitor of deubiquitylating enzyme USP14 and UCHL5 induces apoptosis in multiple myeloma and overcomes bortezomib resistance. Blood 274 24319254
2006 A novel proteasome interacting protein recruits the deubiquitinating enzyme UCH37 to 26S proteasomes. The EMBO journal 217 16990800
2006 hRpn13/ADRM1/GP110 is a novel proteasome subunit that binds the deubiquitinating enzyme, UCH37. The EMBO journal 207 17139257
2005 The deubiquitinating enzyme UCH37 interacts with Smads and regulates TGF-beta signalling. Oncogene 156 16027725
2008 Distinct modes of regulation of the Uch37 deubiquitinating enzyme in the proteasome and in the Ino80 chromatin-remodeling complex. Molecular cell 127 18922472
2015 Mechanism of UCH-L5 activation and inhibition by DEUBAD domains in RPN13 and INO80G. Molecular cell 106 25702870
2015 Structural basis for the activation and inhibition of the UCH37 deubiquitylase. Molecular cell 101 25702872
2010 Regulators of the proteasome pathway, Uch37 and Rpn13, play distinct roles in mouse development. PloS one 81 21048919
2017 Structure of the Rpn13-Rpn2 complex provides insights for Rpn13 and Uch37 as anticancer targets. Nature communications 73 28598414
2004 Uch2/Uch37 is the major deubiquitinating enzyme associated with the 26S proteasome in fission yeast. Journal of molecular biology 73 15533439
2020 Proteasome-Bound UCH37/UCHL5 Debranches Ubiquitin Chains to Promote Degradation. Molecular cell 67 33156996
2012 Expression and clinical significance of UCH37 in human esophageal squamous cell carcinoma. Digestive diseases and sciences 58 22615012
2015 Targeted inhibition of the deubiquitinating enzymes, USP14 and UCHL5, induces proteotoxic stress and apoptosis in Waldenström macroglobulinaemia tumour cells. British journal of haematology 57 25691154
2016 Coinhibition of the deubiquitinating enzymes, USP14 and UCHL5, with VLX1570 is lethal to ibrutinib- or bortezomib-resistant Waldenstrom macroglobulinemia tumor cells. Blood cancer journal 53 27813535
2016 The Proteasome Ubiquitin Receptor hRpn13 and Its Interacting Deubiquitinating Enzyme Uch37 Are Required for Proper Cell Cycle Progression. The Journal of biological chemistry 49 26907685
2018 The deubiquitinase UCHL5/UCH37 positively regulates Hedgehog signaling by deubiquitinating Smoothened. Journal of molecular cell biology 48 28992318
2012 A common ancestry for BAP1 and Uch37 regulators. Bioinformatics (Oxford, England) 48 22645167
2020 LncRNA DRAIC inhibits proliferation and metastasis of gastric cancer cells through interfering with NFRKB deubiquitination mediated by UCHL5. Cellular & molecular biology letters 42 32351584
2011 Crystal structure of the catalytic domain of UCHL5, a proteasome-associated human deubiquitinating enzyme, reveals an unproductive form of the enzyme. The FEBS journal 41 21995438
2011 Structural characterization of human Uch37. Proteins 37 21953935
2009 Crystal structure of the de-ubiquitinating enzyme UCH37 (human UCH-L5) catalytic domain. Biochemical and biophysical research communications 37 19836345
2020 Ubiquitin C-Terminal Hydrolase L5 (UCHL5) Accelerates the Growth of Endometrial Cancer via Activating the Wnt/β-Catenin Signaling Pathway. Frontiers in oncology 36 32596150
2015 Activity-Based Proteomic Profiling of Deubiquitinating Enzymes in Salmonella-Infected Macrophages Leads to Identification of Putative Function of UCH-L5 in Inflammasome Regulation. PloS one 36 26267804
2021 Deubiquitination and Activation of the NLRP3 Inflammasome by UCHL5 in HCV-Infected Cells. Microbiology spectrum 31 34431717
2015 Regulation of E2 promoter binding factor 1 (E2F1) transcriptional activity through a deubiquitinating enzyme, UCH37. The Journal of biological chemistry 30 26396186
2014 Mechanism of the Rpn13-induced activation of Uch37. Protein & cell 30 24752541
2010 Early phase TGFβ receptor signalling dynamics stabilised by the deubiquitinase UCH37 promotes cell migratory responses. The international journal of biochemistry & cell biology 30 21187158
2022 A cryptic K48 ubiquitin chain binding site on UCH37 is required for its role in proteasomal degradation. eLife 28 35451368
2021 Branched ubiquitin chain binding and deubiquitination by UCH37 facilitate proteasome clearance of stress-induced inclusions. eLife 26 34761751
2020 Impact of Losing hRpn13 Pru or UCHL5 on Proteasome Clearance of Ubiquitinated Proteins and RA190 Cytotoxicity. Molecular and cellular biology 25 32631902
2019 The proteasome deubiquitinase inhibitor bAP15 downregulates TGF-β/Smad signaling and induces apoptosis via UCHL5 inhibition in ovarian cancer. Oncotarget 25 31666925
2015 Structural plasticity allows UCH37 to be primed by RPN13 or locked down by INO80G. Molecular cell 25 25747657
2023 METTL14/YTHDF1 axis-modified UCHL5 aggravates atherosclerosis by activating the NLRP3 inflammasome. Experimental cell research 22 37044315
2022 UCHL5 Promotes Proliferation and Migration of Bladder Cancer Cells by Activating c-Myc via AKT/mTOR Signaling. Cancers 22 36428630
2020 Deubiquitinase UCHL5 is elevated and associated with a poor clinical outcome in lung adenocarcinoma (LUAD). Journal of Cancer 21 33046988
2022 Deubiquitinase UCHL5 stabilizes ELK3 to potentiate cancer stemness and tumor progression in pancreatic adenocarcinoma (PAAD). Experimental cell research 20 36328194
2001 Identification of two proteins, S14 and UIP1, that interact with UCH37. FEBS letters 20 11163772
2024 Comprehensive pan-cancer analysis indicates UCHL5 as a novel cancer biomarker and promotes cervical cancer progression through the Wnt signaling pathway. Biology direct 18 39702250
2023 Targeting proteasomal deubiquitinases USP14 and UCHL5 with b-AP15 reduces 5-fluorouracil resistance in colorectal cancer cells. Acta pharmacologica Sinica 18 37528233
2022 The UCHL5 inhibitor b-AP15 overcomes cisplatin resistance via suppression of cancer stemness in urothelial carcinoma. Molecular therapy oncolytics 18 36090476
2013 Stabilization of an unusual salt bridge in ubiquitin by the extra C-terminal domain of the proteasome-associated deubiquitinase UCH37 as a mechanism of its exo specificity. Biochemistry 18 23617878
2019 Inactive USP14 and inactive UCHL5 cause accumulation of distinct ubiquitinated proteins in mammalian cells. PloS one 17 31703099
2017 UCHL5 expression associates with improved survival in lymph-node-positive rectal cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 16 28681694
2023 PTIR1 acts as an isoform of DDX58 and promotes tumor immune resistance through activation of UCHL5. Cell reports 15 37934668
2023 NLRP3 Regulates Mandibular Healing through Interaction with UCHL5 in MSCs. International journal of biological sciences 13 36778113
2022 UCHL5 controls β-catenin destruction complex function through Axin1 regulation. Scientific reports 12 35256667
2024 UCHL5 promotes hepatocellular carcinoma progression by promoting glycolysis through activating Wnt/β-catenin pathway. BMC cancer 8 38773433
2022 Treatment with b-AP15 to Inhibit UCHL5 and USP14 Deubiquitinating Activity and Enhance p27 and Cyclin E1 for Tumors with p53 Deficiency. Technology in cancer research & treatment 8 35971329
2019 Proteasomal deubiquitinase UCH37 inhibits degradation of β-catenin and promotes cell proliferation and motility. Acta biochimica et biophysica Sinica 8 30726867
2022 A ubiquitinome analysis to study the functional roles of the proteasome associated deubiquitinating enzymes USP14 and UCH37. Journal of proteomics 7 35489684
2022 Inhibition of proteasomal deubiquitinases USP14 and UCHL5 overcomes tyrosine kinase inhibitor resistance in chronic myeloid leukaemia. Clinical and translational medicine 7 36082692
2024 Interference with ANXA8 inhibits the malignant progression of ovarian cancer by suppressing the activation of the Wnt/β-catenin signaling pathway via UCHL5. Aging 5 39068672
2023 LncRNA CRNDE binds hnRNPA1 to facilitate carbon monoxide poisoning-induced delayed encephalopathy via inhibiting UCHL5-mediated SMO deubiquitination. Metabolic brain disease 5 36648699
2023 ADRM1/RPN13 attenuates cartilage extracellular matrix degradation via enhancing UCH37-mediated ALK5 deubiquitination. International journal of biological macromolecules 5 37406898
2023 The TGF-β/UCHL5/Smad2 Axis Contributes to the Pathogenesis of Placenta Accreta. International journal of molecular sciences 5 37762005
2025 USP14 and UCHL5 synergistically deubiquitinate PKCα and translocate NF-κB to promote the progression of anaplastic thyroid cancer. Cell death & disease 4 40804247
2021 The CDK4/6-UCHL5-BRD4 axis confers resistance to BET inhibitors in MLL-rearranged leukemia cells by suppressing BRD4 protein degradation. Biochemical and biophysical research communications 4 34954522
2020 Synthesis and evaluation of tiaprofenic acid-derived UCHL5 deubiquitinase inhibitors. Bioorganic & medicinal chemistry 4 33341501
2025 Impairment of proteasome-associated deubiquitinating enzyme Uchl5/UBH-4 affects autophagy. Biology open 3 39912491
2016 Isolation and Characterization of RNA Aptamers against a Proteasome-Associated Deubiquitylating Enzyme UCH37. Chembiochem : a European journal of chemical biology 3 27930845
2025 In vivo CRISPR screening in head and neck cancer reveals Uchl5 as an immunotherapy target. Nature communications 2 41022734
2022 Inhibiting UCH-L5: Rational Design of a Cyclic Ubiquitin-Based Peptide Inhibitor. Frontiers in molecular biosciences 2 35720124
2009 Characterization and tissue expression of channel catfish (Ictalurus punctatus Rafinesque, 1818) ubiquitin carboxyl-terminal hydrolase L5 (UCHL5) cDNA. Molecular biology reports 2 19266312
2026 Quinoxaline-based UCHL5 inhibitor as a next-generation proteasome-targeting anticancer agent beyond 20S inhibition. Journal of advanced research 1 41679601
2024 Proteasome associated function of UCH37 is evolutionarily conserved in Plasmodium parasites. Scientific reports 1 39604441
2018 [Influence of UCHL5 on proliferation and apoptosis of SW527 breast cancer cells]. Zhonghua zhong liu za zhi [Chinese journal of oncology] 1 30605979
2026 UCHL5 suppresses thyroid carcinoma progression via ZRANB1 stabilization and ferroptosis regulation. Cancer biology & therapy 0 42037453
2025 Site-Specific Nanobody Inhibitors of the Proteasomal Deubiquitinase UCH37. bioRxiv : the preprint server for biology 0 40832226
2025 Proteasomal deubiquitinating enzyme USP14/UCHL5 inhibitor bAP15 suppresses endoplasmic reticulum stress-mediated apoptosis and tumor growth in human chondrosarcoma. American journal of cancer research 0 41113965
2024 Targeting USP14/UCHL5: A Breakthrough Approach to Overcoming Treatment-Resistant FLT3-ITD-Positive AML. International journal of molecular sciences 0 39408703
2022 Corrigendum: Ubiquitin C-Terminal hydrolase L5 (UCHL5) accelerates the growth of endometrial cancer via activating the Wnt/β-catenin signaling pathway. Frontiers in oncology 0 36059647

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