Affinage

USP8

Ubiquitin carboxyl-terminal hydrolase 8 · UniProt P40818

Length
1118 aa
Mass
127.5 kDa
Annotated
2026-06-11
100 papers in source corpus 57 papers cited in narrative 57 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

USP8 (UBPY) is a multidomain deubiquitinating isopeptidase that cleaves both K48- and K63-linked polyubiquitin chains and governs the ubiquitin economy of the endosomal system, where it controls receptor trafficking, recycling, and lysosomal degradation (PMID:9628861, PMID:16520378). It is recruited to endosomes through an N-terminal MIT domain that binds ESCRT-III CHMP proteins (CHMP1A/1B/7); this localization is required for its function but dispensable for catalysis, and the enzyme engages the ESCRT-0 machinery by binding STAM1/2 SH3 domains through central RXXK motifs, with STAM in turn stimulating its activity (PMID:17711858, PMID:20736164). At endosomes USP8 deubiquitinates the cargo receptor EGFR and stabilizes ESCRT components such as STAM and Hrs to set receptor sorting dynamics, and it cooperates with HD-PTP/PTPN23 to hand EGFR from ESCRT-0 to ESCRT-III for delivery into intralumenal vesicles (PMID:16120644, PMID:16520378, PMID:20736164, PMID:23477725, PMID:24574010). Beyond EGFR, USP8 deubiquitinates a broad panel of membrane proteins and channels—CXCR4, VEGFR2, BACE1, ENaC, KCa3.1, the leptin receptor, and TβRII—to oppose their lysosomal degradation and tune their surface abundance and downstream signaling (PMID:20876529, PMID:27302062, PMID:23297398, PMID:26459808, PMID:31199479, PMID:35811497). Its catalytic output is gated by phosphorylation-dependent 14-3-3 binding at a Ser680/Ser718 motif that inhibits activity during interphase and is relieved in M phase, while EGFR/Src-mediated tyrosine phosphorylation at Tyr717/Tyr810 elevates activity (PMID:17720156, PMID:29472535, PMID:29473952). Gain-of-function USP8 mutations clustered in the 14-3-3 motif cause Cushing's disease by disrupting 14-3-3 inhibition, enhancing EGFR deubiquitination and sustaining EGF signaling and POMC/ACTH expression in corticotroph adenomas (PMID:25485838, PMID:25675982). USP8 also extends to non-endosomal substrates: it removes K6-linked chains from parkin to enable mitophagy (PMID:25216678), deubiquitinates SHANK3 and AMPARs at synapses (PMID:25505317, PMID:29735556), processes K63 chains on α-synuclein and BRIT1 (PMID:25733871, PMID:27444016), and stabilizes effectors such as GPX4, OGT/SLC7A11, β-catenin, and Nrf2 (PMID:38598341, PMID:37867237, PMID:37311739, PMID:37639742). By restraining endosomal K63-ubiquitin accumulation, USP8 acts as a gatekeeper preventing TAB2/3–TAK1–NF-κB and p62–Keap1–Nrf2 signaling from being aberrantly triggered from endosomes (PMID:38180476).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1998 High

    Established that USP8 is a catalytically active ubiquitin isopeptidase whose abundance and activity are coupled to cell proliferation, framing it as a regulator of the ubiquitin-proteasome system rather than a passive enzyme.

    Evidence in vitro ubiquitin cleavage with recombinant protein plus antisense microinjection with S-phase readout

    PMID:9628861

    Open questions at the time
    • No substrate identified at this stage
    • Mechanism linking activity to S-phase entry undefined
  2. 2000 High

    Connected USP8 to endocytic trafficking by identifying its non-canonical SH3-binding motif interaction with the ESCRT-0 adaptor STAM, anchoring it to growth factor receptor complexes at early endosomes.

    Evidence Far Western screening and mutagenic mapping of the SH3-binding motif with in vitro binding assays

    PMID:10982817

    Open questions at the time
    • Functional consequence of the STAM interaction not yet demonstrated
    • Endosomal recruitment determinant not yet mapped
  3. 2001 Medium

    Showed USP8 can act as a stabilizing deubiquitinase for a binding partner (CDC25Mm/Ras-GRF1), extending its role beyond chain disassembly to controlling substrate half-life.

    Evidence yeast two-hybrid, GST pulldown, Co-IP and co-transfection ubiquitination assay

    PMID:11500497

    Open questions at the time
    • Single lab, ortholog-based
    • Physiological context of CDC25 stabilization unclear
  4. 2004 High

    Demonstrated reciprocal regulation between USP8 and an E3 ligase (Nrdp1), with catalytic activity required to stabilize the partner, defining a DUB–E3 stabilization module.

    Evidence affinity chromatography, Co-IP, domain mapping, and catalytic-mutant stability assays

    PMID:15314180

    Open questions at the time
    • Linkage type of Nrdp1 ubiquitin not defined
    • Downstream consequence of Nrdp1 stabilization not addressed
  5. 2005 High

    Identified EGFR as a direct endosomal substrate, establishing USP8 as a regulator of receptor tyrosine kinase ubiquitination and trafficking.

    Evidence in vitro deubiquitination assay, gain/loss-of-function, and endosomal co-localization of catalytic-dead USP8 with EGFR

    PMID:16120644

    Open questions at the time
    • Directionality of effect on degradation became contested (see #6)
    • Ubiquitin linkage on EGFR not resolved here
  6. 2006 High

    Resolved the biochemical scope and broad endosomal role of USP8: it processes both K48- and K63-linked chains, and its loss destabilizes its partner STAM while disrupting MVE morphology and RTK degradation.

    Evidence siRNA knockdown, in vitro chain-cleavage assays, electron microscopy, and EGFR/Met degradation assays (plus parallel work on Eps15 and Src-dependent tyrosine phosphorylation)

    PMID:16520378 PMID:16771824 PMID:17121848

    Open questions at the time
    • Whether USP8 net promotes or restrains EGFR degradation remained discrepant between studies
    • Mechanism of endosome enlargement upon depletion not fully defined
  7. 2006 High

    Provided the structural framework for USP8 regulation: a helix-swapped N-terminal dimer, a rhodanese–Nrdp1 interface, and a catalytic domain in an autoinhibited closed conformation requiring substrate-induced activation.

    Evidence X-ray crystallography of three USP8 domains and the Nrdp1-rhodanese complex

    PMID:17035239

    Open questions at the time
    • No full-length structure
    • Conformational activation not captured in an active state
  8. 2007 High

    Defined the two pillars of spatial and activity control: the MIT domain mediates ESCRT-III/CHMP-dependent endosomal targeting, while phospho-Ser680-dependent 14-3-3 binding inhibits catalysis and is relieved in M phase.

    Evidence MIT deletion with CHMP binding and siRNA rescue assays; Co-IP/MS, phosphatase and phospho-antibody analyses with in vitro deubiquitination in the presence of 14-3-3

    PMID:17711858 PMID:17720156

    Open questions at the time
    • How cell-cycle phosphatases target Ser680 not defined
    • Relationship between MIT targeting and 14-3-3 gating not integrated
  9. 2010 High

    Mapped USP8 into the ESCRT-0 checkpoint mechanism, showing it sets EGFR and CXCR4 ubiquitination dynamics via multiple STAM-binding RXXK motifs and opposes specific E3 ligases (AIP4) at endosomes.

    Evidence domain mutagenesis of RXXK motifs, Hrs/AIP4 epistasis, endosomal localization, and surface receptor degradation assays; plus ERBB2 chimera and MIT/Src-dependent tyrosine phosphorylation work

    PMID:20736164 PMID:20876529 PMID:21044682

    Open questions at the time
    • Receptor-specific differences in ubiquitin-status dependence unexplained
    • Precise step of the early-to-recycling transition controlled by USP8 not defined
  10. 2012 High

    Generalized USP8 to developmental and circadian signaling, deubiquitinating Smoothened to promote Hedgehog surface accumulation and deubiquitinating CLOCK to restrain CLK/CYC circadian transcription.

    Evidence in vivo Drosophila RNAi screen, ubiquitination assays, Co-IP, localization, and circadian/Hh pathway activity readouts

    PMID:22253573 PMID:23154984

    Open questions at the time
    • Whether Smo/CLOCK effects are endosome-dependent unclear
    • Conservation of CLOCK regulation in mammals not tested
  11. 2013 High

    Expanded the trafficking interactome and substrate range: USP8 is recruited by HD-PTP to transfer EGFR between ESCRT complexes, is itself an RNF41 substrate, and deubiquitinates BACE1, ENaC, and HIF1α to control trafficking, channel surface levels, and ciliogenesis.

    Evidence Co-IP, ILV sorting assays, reciprocal ubiquitination/epistasis, site-specific ubiquitination (BACE1 K501), oocyte electrophysiology, and HIF1α/pVHL epistasis

    PMID:23297398 PMID:23477725 PMID:23750007 PMID:24378640 PMID:27302062

    Open questions at the time
    • How substrate selectivity is achieved among many endosomal cargos unresolved
    • Direct vs indirect effects on HIF1α not fully separated
  12. 2014 High

    Linked USP8 to organelle quality control, DNA repair, immune development, and disease genetics: K6-chain removal from parkin enables mitophagy, K63-chain removal from BRIT1 enables HR repair, T-cell USP8 controls thymocyte maturation, and Cushing's disease mutations cause 14-3-3-resistant gain of function.

    Evidence linkage-specific in vitro deubiquitination, mitophagy and HR assays, conditional/BRUCE-mutant mouse models, exome sequencing, and catalytic/POMC reporter assays

    PMID:24828152 PMID:24894536 PMID:25216678 PMID:25485838 PMID:25733871 PMID:26214742

    Open questions at the time
    • Mechanistic basis of linkage preference (K6, K63) not structurally explained
    • How a single DUB serves such divergent compartments unaddressed
  13. 2015 High

    Established the mechanism of Cushing's disease gain-of-function and broadened substrates: mutations disrupt 14-3-3 to protect EGFR and drive ACTH; USP8 also stabilizes Hrs, FLIPL, and VEGFR2, controlling endosomal sorting, apoptosis, and angiogenic signaling.

    Evidence sequencing cohorts with 14-3-3 disruption and EGFR/POMC assays; Drosophila Ubpy-null genetics; in vitro deubiquitination and apoptosis/DISC assays; VEGFR2 ubiquitination and signaling assays

    PMID:24574010 PMID:25675982 PMID:26459808 PMID:27321185

    Open questions at the time
    • Why corticotrophs are selectively vulnerable to USP8 hyperactivity unclear
    • Isoform selectivity (FLIPL vs FLIPS) mechanism undefined
  14. 2018 High

    Refined activity control and neuronal/structural roles: EGFR directly phosphorylates USP8 at Tyr717/Tyr810 to raise activity in a ciliogenesis-suppressing trichoplein-Aurora A axis, a 14-3-3ζ:phospho-Ser718 structure was solved, and USP8 stabilizes SHANK3 and deubiquitinates ESCRT-III CHMP1B.

    Evidence in vitro kinase assays, phospho-mutant analysis, X-ray crystallography with FP/ITC, neuronal gain/loss-of-function, and Drosophila CHMP1B ubiquitination genetics

    PMID:29472535 PMID:29473952 PMID:29735556 PMID:29933386

    Open questions at the time
    • Integration of tyrosine activation with 14-3-3 inhibition not mechanistically unified
    • Structural basis for catalytic-domain activation still missing
  15. 2019 High

    Positioned USP8 as a regulator of autophagy and metabolic/neuronal signaling: linkage- and site-specific deubiquitination of p62 (K11 at K420) and EPG5 (K63 at K252) tunes autophagic flux, while LepRb deubiquitination links it to leptin/CREB signaling and synaptogenesis.

    Evidence in vitro deubiquitination with linkage/site specificity, autophagic flux assays, Co-IP domain mapping, and receptor/transcriptional/synapse assays

    PMID:30931944 PMID:31199479 PMID:31241013

    Open questions at the time
    • Opposing autophagy effects (p62 vs EPG5) not reconciled into one model
    • Determinants of K11 vs K63 chain selectivity unknown
  16. 2022 High

    Defined USP8 as a node in cancer immune evasion and ESCRT-dependent cytokinesis: it stabilizes TβRII to drive TGF-β-mediated EMT and T-cell exhaustion, its inhibition rewires PD-L1/NF-κB/MHC-I immunity, and germline ESCRT-III deubiquitination controls abscission.

    Evidence Co-IP/ubiquitination assays, EV characterization, EMT and T-cell exhaustion assays, K63/K48 PD-L1 ubiquitination with tumor models, and Drosophila ESCRT-III cytokinesis genetics

    PMID:35361799 PMID:35587967 PMID:35811497

    Open questions at the time
    • Therapeutic window of USP8 inhibition across opposing immune outcomes unclear
    • How ESCRT-III ubiquitination state dictates polymer assembly not fully defined
  17. 2024 High

    Identified USP8 as a guardian of ferroptosis defense and against misdirected endosomal ubiquitin signaling: it stabilizes GPX4, OGT/SLC7A11, β-catenin and Nrf2 to resist ferroptosis, deubiquitinates DDX3X to potentiate cGAS-STING, and prevents endosomal K63-Ub from triggering TAK1-NF-κB and Keap1-Nrf2 inflammation.

    Evidence Co-IP, site/linkage-specific ubiquitination assays, conditional KO mice, ferroptosis and LLPS assays, and endosomal K63-Ub/TAB2/p62 recruitment epistasis

    PMID:37311739 PMID:37639742 PMID:37867237 PMID:38180476 PMID:38598341 PMID:38795350

    Open questions at the time
    • How oxidative stress mechanistically inactivates USP8 to release endosomal signaling not fully defined
    • Hierarchy among the many ferroptosis-relevant substrates unestablished

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how a single deubiquitinase achieves substrate- and linkage-selectivity across endosomes, mitochondria, the nucleus, synapses, and stress granules, and how its competing phospho/tyrosine/sulfhydration inputs are integrated into a unified activation logic.
  • No structural model of substrate-specificity determinants
  • No integrated regulatory model spanning 14-3-3, tyrosine phosphorylation, SLK-S716, and S-sulfhydration
  • Compartment-specific targeting beyond the MIT/ESCRT axis undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 10 GO:0016787 hydrolase activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005768 endosome 6 GO:0005829 cytosol 2
Pathway
R-HSA-392499 Metabolism of proteins 6 R-HSA-162582 Signal Transduction 5 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-168256 Immune System 3 R-HSA-9612973 Autophagy 3
Partners
14-3-3CHMP1BEGFRHD-PTPNRDP1PARKINRNF41STAM
Complex memberships
BRUCE-USP8-BRIT1 complexESCRT-0 (STAM/Hrs)ESCRT-III (CHMP)USP8-Nrdp1-Clec16a complex

Evidence

Reading pass · 57 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 USP8/UBPY is a ubiquitin isopeptidase that cleaves linear and isopeptide-linked ubiquitin chains both as a recombinant protein and upon immunoprecipitation from cell extracts; its levels accumulate upon growth stimulation and its inhibition by antisense prevents S-phase entry, indicating a role in regulating the ubiquitin-proteasome pathway during cell proliferation. In vitro ubiquitin cleavage assay with recombinant protein, immunoprecipitation followed by activity assay, antisense microinjection with S-phase readout The EMBO journal High 9628861
2000 USP8/UBPY interacts with the SH3 domain of Hrs-binding protein (STAM) via a novel non-canonical SH3-binding motif PX(V/I)(D/N)RXXKP, linking it to endocytic trafficking of growth factor receptor complexes through early endosomes. Far Western screening, mutagenic analysis of SH3 binding motif, in vitro binding assays The Journal of biological chemistry High 10982817
2001 Mouse UBPy (USP8 ortholog) interacts with the Ras GEF CDC25(Mm)/Ras-GRF1 via the N-terminal domain of CDC25(Mm), deubiquitinates CDC25(Mm) in vivo, and increases its protein half-life. Yeast two-hybrid screen, GST pulldown in vitro, co-immunoprecipitation in mammalian cells, ubiquitination assay by co-transfection The Journal of biological chemistry Medium 11500497
2004 USP8 physically interacts with the E3 ubiquitin ligase Nrdp1 via its rhodanese and catalytic domains, deubiquitinates Nrdp1, and markedly enhances Nrdp1 stability; a catalytically inactive USP8 point mutant destabilizes endogenous Nrdp1. Affinity chromatography, co-immunoprecipitation, domain-mapping with deletion constructs, catalytic mutant overexpression, protein stability assay Molecular and cellular biology High 15314180
2005 USP8/UBPY deubiquitinates EGFR on endosomes in vitro and in vivo; overexpression reduces EGFR ubiquitination and delays EGF-stimulated EGFR degradation, while RNAi depletion of UBPY leads to elevated EGFR ubiquitination and accelerated degradation; catalytically inactive UBPY localizes to endosomes overlapping with EGFR. Immunopurification followed by in vitro deubiquitination assay, overexpression, RNAi knockdown, immunofluorescence co-localization on endosomes Molecular biology of the cell High 16120644
2006 USP8/UBPY processes Lys-48- and Lys-63-linked polyubiquitin chains in vitro; its knockdown causes global increase in ubiquitinated proteins, accumulation of ubiquitin on enlarged multivesicular endosomes, and strongly inhibits degradation of EGFR and Met receptor tyrosine kinases; depletion also dramatically destabilizes its binding partner STAM. siRNA knockdown, in vitro ubiquitin chain cleavage assay, electron microscopy of endosomes, receptor degradation assay The Journal of biological chemistry High 16520378
2006 USP8/UBPY deubiquitinates EGFR to promote (not inhibit) its lysosomal degradation; dominant-negative UBPY mutants cause EGFR hyperubiquitination, alter EGFR expression levels and degradation intermediates, and affect downstream MAPK signaling; UBPY is a substrate for Src-family tyrosine kinases activated by EGFR and constitutively co-precipitates with EGFR. Dominant-negative mutant overexpression (C748A, truncation constructs), co-immunoprecipitation, ubiquitination assay, MAPK signaling readout The Journal of biological chemistry Medium 17121848
2006 USP8/UBPY deubiquitinates Eps15 in vitro; inactivation of UBPY causes elevated Eps15 monoubiquitination and its accumulation on aberrant multivesicular endosomes, indicating UBPY regulates endosomal ubiquitin levels and endosome morphology. Catalytic-inactive mutant overexpression, RNAi knockdown, in vitro deubiquitination assay, immunofluorescence and electron microscopy Traffic Medium 16771824
2006 Crystal structures of three USP8 domains were determined: (1) the N-terminal domain forms a homodimer with a novel fold via helix-swapping; (2) the rhodanese domain interacts with Nrdp1 via a conserved peptide loop, revealing the structural basis for USP8-Nrdp1 binding; (3) the catalytic domain adopts an inhibited closed conformation with the ubiquitin-binding pocket inaccessible, suggesting substrate-induced conformational activation. X-ray crystallography of three domain structures, structural analysis of NRDP1-rhodanese complex The Journal of biological chemistry High 17035239
2007 USP8/UBPY contains an N-terminal MIT domain that binds CHMP proteins (CHMP1A, CHMP1B, CHMP7) of the ESCRT-III complex; the MIT domain is required for endosomal localization of USP8 but is dispensable for catalytic activity; MIT-deleted USP8 cannot rescue STAM from proteasomal degradation or reverse the block to EGFR degradation caused by USP8 depletion; STAM stimulates USP8 deubiquitinase activity. MIT domain identification and deletion mutagenesis, CHMP binding assays, siRNA rescue experiments, STAM activity stimulation assay The Journal of biological chemistry High 17711858
2007 14-3-3 proteins (ε, γ, ζ) bind USP8 in a phosphorylation-dependent manner at Ser680 within the consensus motif RSYS(680)SP; 14-3-3 binding inhibits USP8 deubiquitinating activity toward polyubiquitin chains and EGFR in vitro; during M phase, USP8 is dephosphorylated at Ser680, dissociates from 14-3-3, and displays enhanced activity. Co-immunoprecipitation followed by mass spectrometry, phosphatase treatment, metabolic 32P labeling, phospho-specific antibody, peptide competition, in vitro deubiquitination assay with 14-3-3 Experimental cell research High 17720156
2010 USP8 depletion accelerates EGFR degradation via an Hrs-dependent pathway; catalytically inactive USP8 causes EGFR hyperubiquitination and endosomal accumulation; USP8 interacts with STAM1/2 SH3 domains via three RXXK motifs in its central region; the USP8·STAM complex regulates EGFR ubiquitination dynamics at early endosomes, with USP8-mediated deubiquitination slowing EGFR progression past the early-to-recycling endosome circuit. USP8 depletion, catalytic mutant overexpression, domain mutagenesis of RXXK motifs, co-immunoprecipitation, endosomal localization assays, receptor degradation assays The Journal of biological chemistry High 20736164
2010 USP8 depletion stabilizes CXCR4 on the cell surface and attenuates receptor degradation without affecting CXCR4 ubiquitination status; USP8 functionally opposes the E3 ligase AIP4 at the ESCRT-0 checkpoint to regulate ESCRT-0 ubiquitination and promote CXCR4 trafficking. siRNA knockdown, surface receptor degradation assay, ubiquitination analysis, endosomal colocalization, epistasis with AIP4 The Journal of biological chemistry Medium 20876529
2010 USP8 interacts with ERBB2 (HER-2) indirectly through a chimeric EGFR-ErbB2 construct; catalytically inactive USP8 (C748A) enhances EGFR-ErbB2 ubiquitination both with and without EGF stimulation; USP8 is tyrosine phosphorylated upon EGFR-ErbB2 activation in a Src- and EGFR-kinase-dependent, MIT domain-dependent manner. Chimeric receptor co-expression, catalytic mutant overexpression, ubiquitination assay, kinase inhibitor treatment, MIT domain mutant analysis Cellular signalling Medium 21044682
2011 USP8 associates with KCa3.1 channel following endocytosis (detected by DUB Chip protein microarray and confirmed by co-immunoprecipitation); overexpression of wild-type USP8 accelerates channel deubiquitination, while catalytically inactive USP8 or siRNA knockdown enhances accumulation of ubiquitylated KCa3.1 and inhibits channel lysosomal degradation. DUB Chip protein microarray, co-immunoprecipitation, BLAP-tagged receptor with TUBE pulldown, overexpression of WT and catalytic mutant, siRNA knockdown, degradation assay FASEB journal Medium 21828287
2012 USP8 is identified by in vivo RNAi screen as a deubiquitinase that removes ubiquitin from multi-monoubiquitinated Smoothened (Smo) in the Hedgehog pathway; USP8 inactivation increases Smo ubiquitination and attenuates Hh-induced Smo cell-surface accumulation; Hh signaling promotes USP8-Smo interaction via Smo aa625-753 covering PKA/CK1 phosphorylation clusters; USP8 overexpression elevates Smo cell-surface accumulation and promotes Smo away from early endosomes. In vivo RNAi screen in Drosophila, ubiquitination assay, co-immunoprecipitation, immunofluorescence localization, Hh pathway activity assay PLoS biology High 22253573
2012 USP8 deubiquitylates the CLOCK transcription factor in Drosophila circadian neurons; loss of USP8 function or dominant-negative USP8 enhances CLK/CYC transcriptional activity and disrupts circadian molecular oscillations; CLK ubiquitylation cycles robustly peaking at maximal CLK/CYC transcription; USP8 interacts with CLK and its expression is directly activated by CLK/CYC. Loss-of-function RNAi, dominant-negative USP8 expression, CLK ubiquitylation cycling assay, co-immunoprecipitation, circadian locomotor activity assay Genes & development Medium 23154984
2013 HD-PTP/PTPN23 recruits UBPY/USP8 to EGFR at ESCRT-0; USP8 associates with HD-PTP-bound CHMP4B and with HD-PTP directly; UBPY/HD-PTP cooperation transfers EGFR from ESCRT-0 to ESCRT-III and drives EGFR sorting to intralumenal vesicles; USP8 RXXK motifs compete with HD-PTP for STAM2 SH3 binding to facilitate EGFR deubiquitination. Co-immunoprecipitation, siRNA knockdown, sorting to intralumenal vesicle assay, domain-interaction mapping Current biology High 23477725
2013 RNF41 ubiquitylates and reduces levels of USP8 (i.e., USP8 is a substrate of RNF41); USP8 in turn stabilizes RNF41; loss of USP8 mimics RNF41 overexpression effects on leptin receptor and LIF receptor trafficking (stabilization and enhanced ectodomain shedding); USP8 depletion also indirectly destabilizes the ESCRT-0 complex. Co-immunoprecipitation, ubiquitylation assay, siRNA knockdown, receptor trafficking assay, epistasis experiments Journal of cell science Medium 23750007
2013 USP8 depletion reduced levels of endogenous BACE1, increased BACE1 ubiquitination at K501, caused BACE1 accumulation in early and late endosomes/lysosomes, decreased BACE1 in recycling endosomes, and reduced BACE1-mediated APP cleavage and amyloid-β production, establishing USP8 as a deubiquitinase that deubiquitinates BACE1 at K501 to regulate its endosomal trafficking and stability. siRNA knockdown, ubiquitination assay, subcellular fractionation/endosomal localization, APP cleavage assay, Aβ measurement The Journal of biological chemistry Medium 27302062
2013 USP8 regulates epithelial Na+ channel (ENaC) by deubiquitinating ENaC; USP8 increases ENaC current in Xenopus oocytes and surface abundance in HEK293 cells by preventing ENaC lysosomal degradation in the endocytic pathway without affecting endocytosis; co-immunoprecipitation confirmed USP8-ENaC interaction; ENaC cytoplasmic lysine mutants reduce USP8 effects. Xenopus oocyte electrophysiology, HEK293 surface biotinylation, co-immunoprecipitation, ENaC lysine mutant analysis, endocytic sorting assay The Journal of biological chemistry Medium 23297398
2014 USP8 mutations in Cushing's disease cluster in the 14-3-3 binding motif, enhance proteolytic cleavage and catalytic activity of USP8, lead to increased deubiquitination of EGFR impairing its downregulation, sustain EGF signaling, and enhance POMC promoter activity in corticotroph adenomas. Exome sequencing, in vitro catalytic activity assay, EGFR ubiquitination assay, POMC promoter-reporter assay, USP8 cleavage analysis Nature genetics High 25485838
2014 USP8 preferentially removes K6-linked ubiquitin chains from parkin; this deubiquitination is required for efficient recruitment of parkin to depolarized mitochondria and subsequent mitophagy; USP8 knockdown causes persistence of K6-linked ubiquitin conjugates on parkin and delays mitophagy. Co-immunoprecipitation, in vitro deubiquitination assay with K6-linkage specificity, siRNA knockdown, mitophagy assay (parkin translocation, mitochondrial clearance) The EMBO journal High 25216678
2014 BRUCE acts as a scaffold bridging USP8 and BRIT1 in a complex; USP8 catalyzes deubiquitination of K63-linked ubiquitin on BRIT1, which is required for BRIT1 recruitment to DNA double-strand break sites via γ-H2AX; loss of BRUCE or USP8 impairs BRIT1 deubiquitination, BRIT1 foci formation, chromatin relaxation, and homologous recombination repair. Co-immunoprecipitation, in vivo ubiquitination assay, DNA damage foci assay (immunofluorescence), HR repair assay, BRUCE-mutant mouse analysis Proceedings of the National Academy of Sciences High 25733871
2014 USP8 interacts with and deubiquitinates LRIG1; SAIT301 anti-Met antibody triggers Met degradation by inducing LRIG1 ubiquitination through inhibition of USP8-LRIG1 interaction, demonstrating USP8 as a LRIG1-specific deubiquitinase that controls Met degradation efficiency. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, receptor degradation assay Scientific reports Medium 24828152
2014 USP8 depletion in somatic cells causes redistribution of cation-independent mannose-6-phosphate receptor (ci-M6PR) from TGN to endosomes, leading to defective retromer-dependent trafficking and secretion of unprocessed Cathepsin D; this requires USP8 catalytic activity and MIT domain for endosomal localization. siRNA knockdown, siRNA-resistant rescue with WT and mutant USP8, subcellular fractionation, Cathepsin D processing/secretion assay Traffic Medium 24894536
2015 USP8 is a regulatory component of the TCR signalosome that interacts with adaptor Gads and 14-3-3β; caspase-dependent processing of USP8 occurs upon TCR stimulation; T cell-specific USP8 deletion in mice causes defective thymocyte maturation, failure to upregulate IL-7Rα via Foxo1, and development of colitis with impaired regulatory T cell function. Co-immunoprecipitation, T cell-specific conditional knockout mouse, flow cytometry for thymocyte maturation, gene expression analysis, colitis phenotyping Nature immunology High 26214742
2015 Somatic USP8 gain-of-function mutations in Cushing's disease disrupt 14-3-3 protein interaction, elevate USP8 capacity to protect EGFR from lysosomal degradation, result in higher EGFR and POMC/ACTH expression; USP8 knockdown or EGFR blockade attenuates ACTH secretion in primary USP8-mutated tumor cells. Whole-exome and Sanger sequencing, 14-3-3 interaction disruption assay, EGFR protein levels, POMC mRNA levels, siRNA knockdown in primary cultures Cell research High 25675982
2015 In Drosophila, USP8 deubiquitylates and stabilizes Hrs (ESCRT-0); in Ubpy-null cells Hrs becomes ubiquitylated and degraded in lysosomes, disrupting ESCRT-0 sorting machinery and causing accumulation of signaling proteins in enlarged aberrant endosomes. Drosophila Ubpy null genetics, co-immunoprecipitation, ubiquitination assay, endosomal morphology analysis Development Medium 24574010
2015 USP8 deubiquitinates and stabilizes the long isoform of FLIP (FLIPL) but not the short isoform; USP8 depletion induces FLIPL destabilization and promotes death receptor-mediated extrinsic apoptosis via enhanced DISC and TNFR1 complex II formation and caspase-8/3 activation. Co-immunoprecipitation, in vitro deubiquitination assay, siRNA knockdown, apoptosis assays (Annexin V, caspase activity), DISC complex immunoprecipitation Oncogene Medium 27321185
2015 USP8 promotes VEGFR2 deubiquitination; USP8 depletion in endothelial cells alters VEGFR2 ubiquitination and causes VEGFR2 accumulation in endosome-lysosome system with production of a unique extracellular domain proteolytic fragment, and impairs VEGF-A-stimulated signal transduction. siRNA knockdown, VEGFR2 ubiquitination assay, endosomal localization, VEGFR2 proteolytic fragment analysis, VEGF-A signaling readout Traffic Medium 26459808
2016 USP8 interacts and co-localizes with α-synuclein in endosomal membranes and deubiquitinates K63-linked chains from α-synuclein both in cells and after purification; Usp8 knockdown in Drosophila and human cells increases lysosomal degradation of α-synuclein; in dopaminergic neurons, Usp8 protects against α-synuclein-induced locomotor deficits and cell loss. Co-immunoprecipitation, in vitro/in-cell deubiquitination assay with K63 specificity, siRNA knockdown with lysosomal degradation assay, Drosophila genetics (locomotor, neuronal loss) Proceedings of the National Academy of Sciences High 27444016
2016 EGFR kinase directly phosphorylates USP8 on Tyr-717 and Tyr-810; these phosphorylations elevate USP8 deubiquitinase activity, which stabilizes the trichoplein-Aurora A pathway to suppress ciliogenesis; EGFR knockdown and serum starvation induce ciliogenesis through downregulation of this USP8-trichoplein-Aurora A signal. In vitro kinase assay with EGFR and USP8, phospho-specific mutant analysis, trichoplein/Aurora A stability assay, ciliogenesis assay, zebrafish usp8 KO Nature communications High 29472535
2013 USP8 deubiquitinates HIF1α, counteracting pVHL-mediated HIF1α ubiquitination; USP8 maintains basal HIF1α expression in normoxia, and this HIF1α deubiquitination is required for ciliogenesis through repression of Rabaptin5, which controls endosome trafficking. siRNA screen for ciliogenesis genes, HIF1α ubiquitination assay, epistasis with pVHL, ciliogenesis assay, Rabaptin5 expression assay EMBO reports Medium 24378640
2014 NMDAR activation causes dephosphorylation and activation of USP8 in neurons; activated USP8 deubiquitinates AMPARs; surface AMPAR levels and synaptic strength are inversely regulated by Nedd4-1 and USP8; USP8 levels decrease during homeostatic downscaling, while Nedd4-1 increases. NMDAR activation, phosphorylation assay, co-immunoprecipitation, surface AMPAR biotinylation, electrophysiology (synaptic strength), USP8/Nedd4-1 protein level analysis The Journal of neuroscience Medium 25505317
2017 USP8 forms a ubiquitin-dependent tripartite complex with Nrdp1 (E3 ligase) and Clec16a (which encodes an E3 ligase promoting non-degradative ubiquitin conjugates to direct mitophagy effectors); this complex is essential for β-cell mitophagy; lenalidomide inhibits Clec16a and destabilizes the complex, impairing β-cell mitophagy and insulin secretion. Co-immunoprecipitation, ubiquitination assay, mitophagy assay, β-cell oxygen consumption and insulin secretion assay, pharmacological inhibition Diabetes Medium 29180353
2018 Crystal structure of the 14-3-3ζ protein in complex with the USP8 Ser718-phosphorylated motif was determined; fluorescence polarization and isothermal titration calorimetry quantified the interaction affinity; Cushing's disease mutations in USP8 impair 14-3-3 binding. X-ray crystallography, fluorescence polarization, isothermal titration calorimetry FEBS letters High 29473952
2018 USP8 deubiquitinates and stabilizes SHANK3 (and SHANK1) in neurons; USP8 overexpression enhances SHANK3/SHANK1 protein levels via deubiquitination and increases dendritic spine density; USP8 is essential for activity-dependent changes in SHANK3 protein levels. Co-immunoprecipitation, in vitro deubiquitination assay, USP8 overexpression, USP8 knockdown, dendritic spine counting, synaptic activity modulation The Journal of neuroscience Medium 29735556
2018 CHMP1B is ubiquitinated within its flexible loop and is deubiquitinated by USP8; CHMP1B ubiquitination is induced by EGF stimulation; CHMP1B ubiquitination is necessary for EGFR trafficking and wing development in Drosophila; USP8 deubiquitination of CHMP1B may favor its assembly into ESCRT-III polymers. Co-immunoprecipitation, ubiquitination assay, Drosophila genetics (wing phenotype), EGF-stimulated CHMP1B ubiquitination assay PLoS genetics Medium 29933386
2019 USP8 interacts with and deubiquitinates SQSTM1/p62 preferentially removing K11-linked ubiquitin chains at K420 within the UBA domain; this deubiquitination inhibits p62 degradation and suppresses autophagic flux; the K420R mutant abolishes USP8 effects. Co-immunoprecipitation, in vitro deubiquitination assay with linkage specificity, K420R mutant analysis, autophagic flux assay Autophagy High 31241013
2019 USP8 deubiquitinates EPG5 by removing K63-linked ubiquitin chains at K252, leading to enhanced EPG5-LC3 interaction and autophagic flux maintenance in embryonic stem cells; USP8-EPG5 interaction is through the Coiled-coil domain of EPG5. Co-immunoprecipitation (Coiled-coil domain mapping), in vitro deubiquitination assay with K63 specificity, K252 site identification, EPG5-LC3 interaction assay, autophagic flux assay in ESCs Nature communications High 30931944
2019 USP8 interacts with and deubiquitinates TRAF6, TAB2, TAK1, p62, and BECN1; USP8 deubiquitinates K63-linked ubiquitination of TAK1; USP8 knockout in liver cancer cells increases NF-κB activation and autophagy in response to TLR4/LPS stimulation, enhancing cancer progression and metastasis. Co-immunoprecipitation, K63-linked ubiquitination assay of TAK1, USP8 knockout (CRISPR), NF-κB reporter, invasion/metastasis assay, xenograft Translational oncology Medium 34688043
2020 H2S promotes S-sulfhydration of USP8 at specific cysteine residues; S-sulfhydration of USP8 is decreased under hyperglycemia/hyperlipidemia; H2S-mediated USP8 sulfhydration enhances USP8 deubiquitinase activity toward parkin and promotes USP8-parkin interaction, facilitating parkin translocation to mitochondria and mitophagy formation in diabetic cardiomyopathy. S-sulfhydration detection assay, dithiothreitol reversal of sulfhydration, co-immunoprecipitation (USP8-parkin), ubiquitination assay of parkin, mitophagy assay, db/db mouse model Aging and disease Medium 32257541
2020 USP8 inhibition in macrophages increases expression of Nrdp1 (E3 ligase for TLR4), which downregulates TLR4 and MyD88 protein levels and inhibits IKKβ/IκBα phosphorylation, thereby reducing NF-κB p65 nuclear translocation and pro-inflammatory cytokine production; USP8 opposes TLR4/MyD88/NF-κB signaling. In vivo LPS mouse model, intracerebroventricular USP8 administration, TLR4 knockout mice, TLR4 inhibitor, Western blot for NF-κB pathway components, cytokine measurement Brain, behavior, and immunity Medium 32335193
2021 USP8 interacts with and deubiquitinates TAK1 via K63-linked ubiquitination in liver cells; USP8 promotes mRNA stability of USP8 through PTBP1/MALAT1 axis; USP8 stabilizes TAK1 and its depletion promotes TAK1 degradation, pyroptosis, and M1 macrophage polarization contributing to liver fibrosis. Co-immunoprecipitation, protein degradation assay, ubiquitination assay, RNA pulldown, RIP assay, methylated RNA immunoprecipitation, gain/loss-of-function Cell death discovery Medium 34839365
2019 USP8 deubiquitinates the leptin receptor (LepRb), inhibiting its lysosomal degradation and enhancing surface localization; USP8 is in complex with LepRb; leptin stimulation increases USP8 activity and induces USP8 gene expression via CREB-dependent transcription; increased USP8 expression enhances MAPK/ERK pathway activation and glutamatergic synapse formation in hippocampal neurons in a LepRb-dependent manner. Co-immunoprecipitation, surface receptor assay, USP8 activity assay, dominant-negative CREB, shRNA knockdown, synapse formation assay Endocrinology Medium 31199479
2018 USP8 interacts with and deubiquitinates Cx43 (connexin-43), reducing both monoubiquitination and polyubiquitination of Cx43 to prevent autophagy-mediated degradation; USP8 knockdown decreases Cx43 protein levels and suppresses intercellular dye transfer (gap junction communication). Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, dye transfer assay for gap junction function The Journal of biological chemistry Medium 29626091
2019 Inhibition of USP8 in Drosophila PINK1 KO model normalizes elevated Mitofusin (MFN) protein levels; a targeted DUB RNAi screen identified USP8 as prominently influencing MFN levels; USP8 inhibition in PINK1-deficient models improves mitochondrial function, locomotor performance, lifespan, and prevents dopaminergic neuron loss. RNAi DUB screen for MFN levels, genetic USP8 inhibition, pharmacological USP8 inhibition, PINK1 KO Drosophila, mitochondrial function assay, dopaminergic neuron counting Life science alliance Medium 30988163
2022 USP8 directly deubiquitinates and stabilizes the type II TGF-β receptor TβRII, leading to increased TβRII expression at the plasma membrane and in tumor-derived extracellular vesicles; USP8 promotes TGF-β/SMAD-induced EMT, invasion, and metastasis; elevated TβRII+ extracellular vesicles mediate T cell exhaustion; pharmacological USP8 inhibition reduces TβRII stability and TβRII+ circulating EVs. Co-immunoprecipitation, ubiquitination assay, TβRII surface expression assay, extracellular vesicle isolation and characterization, EMT/invasion assay, T cell exhaustion assay The EMBO journal High 35811497
2022 USP8 inhibition increases PD-L1 protein abundance by elevating TRAF6-mediated K63-linked ubiquitination of PD-L1 to antagonize its K48-linked ubiquitination and degradation; USP8 inhibition also activates NF-κB signaling to trigger innate immune response and MHC-I expression. K63/K48 ubiquitination assays of PD-L1, TRAF6 pathway analysis, NF-κB activation assay, MHC-I expression assay, tumor immunotherapy mouse models Nature communications High 35361799
2022 USP8 deubiquitinates ESCRT-III proteins CHMP2B and Shrub/CHMP4 in Drosophila germline; loss of USP8 causes ectopic ESCRT-III recruitment at intercellular bridges converting incomplete cell divisions to complete cytokinesis; a Shrub/CHMP4 variant that cannot be ubiquitinated fails to localize at abscission bridges; overexpression of USP8 in germline stem cells converts complete to incomplete cytokinesis. Drosophila genetics (usp8 mutant, overexpression), ubiquitination-resistant CHMP4 mutant analysis, ESCRT localization at intercellular bridges, cytokinesis assay Science High 35587967
2024 USP8 interacts with and deubiquitinates GPX4, leading to GPX4 stabilization; USP8 inhibition destabilizes GPX4 and sensitizes cancer cells to ferroptosis; homozygous USP8 deletion in intestinal epithelial cells causes lipid peroxidation and cell death. Co-immunoprecipitation, ubiquitination/stability assay, USP8 conditional knockout mouse, ferroptosis assay (lipid peroxidation), in vitro cancer cell ferroptosis, in vivo tumor model Proceedings of the National Academy of Sciences High 38598341
2024 USP8 is recruited to stress granules (SGs) upon dsDNA stimulation and cleaves K27-linked ubiquitin chains from the intrinsically disordered region (IDR) of DDX3X, enhancing DDX3X condensation and liquid-liquid phase separation; enhanced DDX3X LLPS promotes cGAS phase separation and activation, potentiating cGAS-STING signaling and type I interferonopathy. Co-immunoprecipitation, K27-linkage-specific ubiquitination assay of DDX3X, stress granule localization assay, LLPS assay, cGAS activation assay, USP8 inhibitor in Trex1-/- mice Cell reports High 38795350
2024 USP8 depletion causes aberrant accumulation of K63-linked ubiquitin chains on endosomes; TAB2/3 (decoder for K63-Ub) is recruited to endosomes, activating TAK1-NF-κB signaling; p62 is also recruited to endosomes activating Keap1-Nrf2; oxidative stress suppresses USP8 activity, causing K63-Ub accumulation on endosomes and TAB2 recruitment triggering inflammatory cytokine expression. USP8 depletion, K63-linked ubiquitin chain accumulation assay on endosomes, TAB2/p62 endosomal recruitment assay, NF-κB and Nrf2 reporter assays, oxidative stress treatment The Journal of cell biology High 38180476
2023 USP8 stabilizes O-GlcNAc transferase (OGT) by inhibiting K48-specific poly-ubiquitination of OGT at K117; SLK-mediated phosphorylation of USP8 at S716 is required for USP8-OGT interaction; OGT O-GlcNAcylates SLC7A11 at Ser26, enabling cystine import; USP8 inhibition reduces OGT stability, decreases SLC7A11 O-GlcNAcylation, and induces ferroptosis in HCC. Co-immunoprecipitation, K48-specific ubiquitination assay at OGT K117, phosphorylation site mutagenesis (S716), O-GlcNAcylation assay of SLC7A11 at Ser26, cystine import assay, ferroptosis assay Advanced science High 37867237
2023 USP8 directly deubiquitinates β-catenin, inhibiting K48-specific poly-ubiquitination, and stabilizes β-catenin protein; the USP domain of USP8 interacts with the ARM domain of β-catenin; USP8 depletion decreases β-catenin protein levels, β-catenin target gene expression, and promotes ferroptosis resistance. Co-immunoprecipitation (domain mapping of USP8 USP domain and β-catenin ARM domain), K48-specific ubiquitination assay, TOP-luciferase reporter, siRNA knockdown, ferroptosis assay Cell death & disease Medium 37311739
2023 USP8 directly interacts with and deubiquitinates Nrf2 by removing K48-linked polyubiquitin chains, stabilizing Nrf2 expression; this enhances Nrf2 signaling activation and promotes gemcitabine resistance in pancreatic cancer. Co-immunoprecipitation, K48-specific ubiquitination assay of Nrf2, siRNA/overexpression, in vivo xenograft Biomedicine & pharmacotherapy Medium 37639742

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Mutations in the deubiquitinase gene USP8 cause Cushing's disease. Nature genetics 435 25485838
2014 USP8 regulates mitophagy by removing K6-linked ubiquitin conjugates from parkin. The EMBO journal 323 25216678
2015 Recurrent gain-of-function USP8 mutations in Cushing's disease. Cell research 265 25675982
2005 Regulation of epidermal growth factor receptor down-regulation by UBPY-mediated deubiquitination at endosomes. Molecular biology of the cell 225 16120644
2006 The ubiquitin isopeptidase UBPY regulates endosomal ubiquitin dynamics and is essential for receptor down-regulation. The Journal of biological chemistry 216 16520378
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. The Journal of biological chemistry 193 10982817
1998 UBPY: a growth-regulated human ubiquitin isopeptidase. The EMBO journal 159 9628861
2007 The MIT domain of UBPY constitutes a CHMP binding and endosomal localization signal required for efficient epidermal growth factor receptor degradation. The Journal of biological chemistry 140 17711858
2006 Amino-terminal dimerization, NRDP1-rhodanese interaction, and inhibited catalytic domain conformation of the ubiquitin-specific protease 8 (USP8). The Journal of biological chemistry 134 17035239
2004 Stabilization of the E3 ubiquitin ligase Nrdp1 by the deubiquitinating enzyme USP8. Molecular and cellular biology 134 15314180
2021 The METTL3/MALAT1/PTBP1/USP8/TAK1 axis promotes pyroptosis and M1 polarization of macrophages and contributes to liver fibrosis. Cell death discovery 128 34839365
2022 USP8 inhibition reshapes an inflamed tumor microenvironment that potentiates the immunotherapy. Nature communications 120 35361799
2013 USP8 is a novel target for overcoming gefitinib resistance in lung cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 120 23748694
2006 UBPY-mediated epidermal growth factor receptor (EGFR) de-ubiquitination promotes EGFR degradation. The Journal of biological chemistry 120 17121848
2015 The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing's disease. European journal of endocrinology 119 26578638
2024 USP8-governed GPX4 homeostasis orchestrates ferroptosis and cancer immunotherapy. Proceedings of the National Academy of Sciences of the United States of America 117 38598341
2012 USP8 promotes smoothened signaling by preventing its ubiquitination and changing its subcellular localization. PLoS biology 117 22253573
2016 Deubiquitinase Usp8 regulates α-synuclein clearance and modifies its toxicity in Lewy body disease. Proceedings of the National Academy of Sciences of the United States of America 111 27444016
2023 Targeting USP8 Inhibits O-GlcNAcylation of SLC7A11 to Promote Ferroptosis of Hepatocellular Carcinoma via Stabilization of OGT. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 101 37867237
2006 A deubiquitinating enzyme UBPY regulates the level of protein ubiquitination on endosomes. Traffic (Copenhagen, Denmark) 100 16771824
2013 Recruitment of UBPY and ESCRT exchange drive HD-PTP-dependent sorting of EGFR to the MVB. Current biology : CB 97 23477725
2010 Regulation of epidermal growth factor receptor ubiquitination and trafficking by the USP8·STAM complex. The Journal of biological chemistry 89 20736164
2019 The ubiquitin-specific protease USP8 directly deubiquitinates SQSTM1/p62 to suppress its autophagic activity. Autophagy 87 31241013
2019 Driver mutations in USP8 wild-type Cushing's disease. Neuro-oncology 85 31222332
2007 14-3-3-dependent inhibition of the deubiquitinating activity of UBPY and its cancellation in the M phase. Experimental cell research 82 17720156
2001 Cloning and characterization of mouse UBPy, a deubiquitinating enzyme that interacts with the ras guanine nucleotide exchange factor CDC25(Mm)/Ras-GRF1. The Journal of biological chemistry 81 11500497
2022 USP8 promotes cancer progression and extracellular vesicle-mediated CD8+ T cell exhaustion by deubiquitinating the TGF-β receptor TβRII. The EMBO journal 78 35811497
2017 Somatic USP8 Gene Mutations Are a Common Cause of Pediatric Cushing Disease. The Journal of clinical endocrinology and metabolism 77 28505279
2020 Exogenous H2S Promoted USP8 Sulfhydration to Regulate Mitophagy in the Hearts of db/db Mice. Aging and disease 75 32257541
2015 The ubiquitin-specific protease USP8 is critical for the development and homeostasis of T cells. Nature immunology 73 26214742
2023 USP8 positively regulates hepatocellular carcinoma tumorigenesis and confers ferroptosis resistance through β-catenin stabilization. Cell death & disease 72 37311739
2014 Synaptic strength is bidirectionally controlled by opposing activity-dependent regulation of Nedd4-1 and USP8. The Journal of neuroscience : the official journal of the Society for Neuroscience 72 25505317
2010 The deubiquitinating enzyme USP8 promotes trafficking and degradation of the chemokine receptor 4 at the sorting endosome. The Journal of biological chemistry 69 20876529
2010 USP8, a regulator of endosomal sorting, is involved in mouse acrosome biogenesis through interaction with the spermatid ESCRT-0 complex and microtubules. Biology of reproduction 67 20130268
2013 HIF1α deubiquitination by USP8 is essential for ciliogenesis in normoxia. EMBO reports 66 24378640
2018 The USP8 mutational status may predict long-term remission in patients with Cushing's disease. Clinical endocrinology 65 29957855
2022 Molecular mechanism of lncRNA SNHG12 in immune escape of non-small cell lung cancer through the HuR/PD-L1/USP8 axis. Cellular & molecular biology letters 64 35658874
2018 EGF receptor kinase suppresses ciliogenesis through activation of USP8 deubiquitinase. Nature communications 62 29472535
2016 The Endosome-associated Deubiquitinating Enzyme USP8 Regulates BACE1 Enzyme Ubiquitination and Degradation. The Journal of biological chemistry 61 27302062
2017 Clec16a, Nrdp1, and USP8 Form a Ubiquitin-Dependent Tripartite Complex That Regulates β-Cell Mitophagy. Diabetes 60 29180353
2019 Ubiquitin-specific protease 8 (USP8/UBPy): a prototypic multidomain deubiquitinating enzyme with pleiotropic functions. Biochemical Society transactions 52 31845722
2016 USP8 suppresses death receptor-mediated apoptosis by enhancing FLIPL stability. Oncogene 50 27321185
2011 Role of ubiquitylation and USP8-dependent deubiquitylation in the endocytosis and lysosomal targeting of plasma membrane KCa3.1. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 49 21828287
2021 USP8 and TP53 Drivers are Associated with CNV in a Corticotroph Adenoma Cohort Enriched for Aggressive Tumors. The Journal of clinical endocrinology and metabolism 48 33221858
2020 USP8 protects against lipopolysaccharide-induced cognitive and motor deficits by modulating microglia phenotypes through TLR4/MyD88/NF-κB signaling pathway in mice. Brain, behavior, and immunity 48 32335193
2021 The oncogenic role of ubiquitin specific peptidase (USP8) and its signaling pathways targeting for cancer therapeutics. Archives of biochemistry and biophysics 45 33600786
2018 Clinical characteristics and surgical outcome in USP8-mutated human adrenocorticotropic hormone-secreting pituitary adenomas. Endocrine 45 30315484
2019 Germline USP8 Mutation Associated With Pediatric Cushing Disease and Other Clinical Features: A New Syndrome. The Journal of clinical endocrinology and metabolism 44 31162547
2018 USP8 Mutations in Pituitary Cushing Adenomas-Targeted Analysis by Next-Generation Sequencing. Journal of the Endocrine Society 44 29600293
2013 Reciprocal cross-regulation between RNF41 and USP8 controls cytokine receptor sorting and processing. Journal of cell science 44 23750007
2017 Somatic USP8 mutations are frequent events in corticotroph tumor progression causing Nelson's tumor. European journal of endocrinology 42 28982703
2015 USP8 and PARK2/parkin-mediated mitophagy. Autophagy 42 25700639
2019 USP8 maintains embryonic stem cell stemness via deubiquitination of EPG5. Nature communications 41 30931944
2015 BRUCE regulates DNA double-strand break response by promoting USP8 deubiquitination of BRIT1. Proceedings of the National Academy of Sciences of the United States of America 41 25733871
2012 CLOCK deubiquitylation by USP8 inhibits CLK/CYC transcription in Drosophila. Genes & development 40 23154984
2010 ERBB2 is a target for USP8-mediated deubiquitination. Cellular signalling 40 21044682
2020 SST5 expression and USP8 mutation in functioning and silent corticotroph pituitary tumors. Endocrine connections 39 32101529
2019 Cushing's disease due to somatic USP8 mutations: a systematic review and meta-analysis. Pituitary 39 31273566
2018 CHMP1B is a target of USP8/UBPY regulated by ubiquitin during endocytosis. PLoS genetics 38 29933386
2013 Ubiquitin-specific peptidase 8 (USP8) regulates endosomal trafficking of the epithelial Na+ channel. The Journal of biological chemistry 37 23297398
2015 Decoding the genetic basis of Cushing's disease: USP8 in the spotlight. European journal of endocrinology 36 26012588
1998 An oncogenic fusion product of the phosphatidylinositol 3-kinase p85beta subunit and HUMORF8, a putative deubiquitinating enzyme. Oncogene 36 9582025
2023 piRNA-1742 promotes renal cell carcinoma malignancy by regulating USP8 stability through binding to hnRNPU and thereby inhibiting MUC12 ubiquitination. Experimental & molecular medicine 35 37332045
2022 The deubiquitinase USP8 targets ESCRT-III to promote incomplete cell division. Science (New York, N.Y.) 34 35587967
2019 Impact of USP8 Gene Mutations on Protein Deregulation in Cushing Disease. The Journal of clinical endocrinology and metabolism 34 30844069
2018 Biophysical and structural insight into the USP8/14-3-3 interaction. FEBS letters 33 29473952
2018 USP8 Deubiquitinates SHANK3 to Control Synapse Density and SHANK3 Activity-Dependent Protein Levels. The Journal of neuroscience : the official journal of the Society for Neuroscience 33 29735556
2022 Improved pasireotide response in USP8 mutant corticotroph tumours in vitro. Endocrine-related cancer 32 35686696
2015 VEGFR2 Trafficking, Signaling and Proteolysis is Regulated by the Ubiquitin Isopeptidase USP8. Traffic (Copenhagen, Denmark) 32 26459808
2024 Stress granule-localized USP8 potentiates cGAS-mediated type I interferonopathies through deubiquitination of DDX3X. Cell reports 29 38795350
2021 Inhibiting USP8 overcomes hepatocellular carcinoma resistance via suppressing receptor tyrosine kinases. Aging 29 34081623
2015 USP8/UBPy-regulated sorting and the development of sperm acrosome: the recruitment of MET. Reproduction (Cambridge, England) 28 25744385
2014 USP8 modulates ubiquitination of LRIG1 for Met degradation. Scientific reports 27 24828152
2021 METTL3 Regulates Ossification of the Posterior Longitudinal Ligament via the lncRNA XIST/miR-302a-3p/USP8 Axis. Frontiers in cell and developmental biology 26 33748113
2014 Ubpy controls the stability of the ESCRT-0 subunit Hrs in development. Development (Cambridge, England) 26 24574010
2014 USP8 controls the trafficking and sorting of lysosomal enzymes. Traffic (Copenhagen, Denmark) 26 24894536
2021 USP8 regulates liver cancer progression via the inhibition of TRAF6-mediated signal for NF-κB activation and autophagy induction by TLR4. Translational oncology 24 34688043
2019 Inhibition of the deubiquitinase USP8 corrects a Drosophila PINK1 model of mitochondria dysfunction. Life science alliance 24 30988163
2019 USP8 Deubiquitinates the Leptin Receptor and Is Necessary for Leptin-Mediated Synapse Formation. Endocrinology 24 31199479
2018 The ubiquitin-specific protease USP8 deubiquitinates and stabilizes Cx43. The Journal of biological chemistry 24 29626091
2022 USP8 inhibitor-induced DNA damage activates cell cycle arrest, apoptosis, and autophagy in esophageal squamous cell carcinoma. Cell biology and toxicology 23 35022897
2021 Genetic Profiling of a Cohort of Italian Patients with ACTH-Secreting Pituitary Tumors and Characterization of a Novel USP8 Gene Variant. Cancers 23 34439178
2022 Discovery of Potent Small-Molecule USP8 Inhibitors for the Treatment of Breast Cancer through Regulating ERα Expression. Journal of medicinal chemistry 22 35786929
2021 USP8, USP48, and BRAF mutations differ in their genotype-phenotype correlation in Asian Indian patients with Cushing's disease. Endocrine 22 34664215
2020 Down-regulation of USP8 Inhibits Cholangiocarcinoma Cell Proliferation and Invasion. Cancer management and research 21 32273758
2020 USP8 Inhibitor Suppresses HER-2 Positive Gastric Cancer Cell Proliferation and Metastasis via the PI3K/AKT Signaling Pathway. OncoTargets and therapy 21 33116578
2023 USP8 promotes gemcitabine resistance of pancreatic cancer via deubiquitinating and stabilizing Nrf2. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 20 37639742
2023 Expanding the spectrum of tyrosine kinase fusions in calcified chondroid mesenchymal neoplasms: Identification of a novel PDGFRA::USP8 gene fusion. Genes, chromosomes & cancer 20 37642440
2021 USP8 inhibitor RA-9 reduces ACTH release and cell growth in tumor corticotrophs. Endocrine-related cancer 20 34086599
2015 The deubiquitinating enzyme UBPy/USP8 interacts with TrkA and inhibits neuronal differentiation in PC12 cells. Experimental cell research 20 25662281
2022 Discovery of Potent OTUB1/USP8 Dual Inhibitors Targeting Proteostasis in Non-Small-Cell Lung Cancer. Journal of medicinal chemistry 19 36221183
2019 USP8 ameliorates cognitive and motor impairments via microglial inhibition in a mouse model of sepsis-associated encephalopathy. Brain research 19 31075263
2020 USP8 Mutations and Cell Cycle Regulation in Corticotroph Adenomas. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 18 32053843
2020 Down-Regulation of USP8 Suppresses HER-3 Positive Gastric Cancer Cells Proliferation. OncoTargets and therapy 18 32848421
2018 Effect of deubiquitinase USP8 on hypoxia/reoxygenation‑induced inflammation by deubiquitination of TAK1 in renal tubular epithelial cells. International journal of molecular medicine 18 30221684
2015 The Deubiquitinating Enzyme UBPY Is Required for Lysosomal Biogenesis and Productive Autophagy in Drosophila. PloS one 18 26571504
2021 USP8 is a Novel Therapeutic Target in Melanoma Through Regulating Receptor Tyrosine Kinase Levels. Cancer management and research 17 34079371
2020 Knockdown of USP8 Inhibits the Growth of Lung Cancer Cells. Cancer management and research 17 33293867
2013 The Usp8 deubiquitination enzyme is post-translationally modified by tyrosine and serine phosphorylation. Cellular signalling 17 23333852
2024 USP8 prevents aberrant NF-κB and Nrf2 activation by counteracting ubiquitin signals from endosomes. The Journal of cell biology 16 38180476

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