Affinage

USP8

Ubiquitin carboxyl-terminal hydrolase 8 · UniProt P40818

Length
1118 aa
Mass
127.5 kDa
Annotated
2026-04-28
100 papers in source corpus 50 papers cited in narrative 50 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

USP8 is a broadly acting deubiquitinase that controls the ubiquitination status, stability, and trafficking fate of diverse substrates spanning receptor tyrosine kinase signaling, endosomal sorting, autophagy, mitophagy, ciliogenesis, synaptic plasticity, innate immunity, and cell division. Its catalytic activity is regulated by multiple post-translational modifications: phosphorylation of Ser680 promotes inhibitory 14-3-3 binding that is relieved during mitosis, EGFR-dependent Tyr717/Tyr810 phosphorylation activates the enzyme to suppress ciliogenesis via trichoplein stabilization, and S-sulfhydration enhances its activity toward parkin to promote mitophagy (PMID:17720156, PMID:29472535, PMID:32257541). USP8 is recruited to endosomes through its MIT domain (which binds CHMP proteins) and RXXK motifs (which bind STAM/ESCRT-0), where it deubiquitinates EGFR, ESCRT-III subunits, and other cargo to govern multivesicular body sorting and receptor recycling versus degradation (PMID:17711858, PMID:16120644, PMID:35587967). Somatic gain-of-function mutations in the 14-3-3 binding motif of USP8 cause Cushing's disease by enhancing EGFR deubiquitination and sustaining POMC transcription in corticotroph adenomas (PMID:25485838).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1998 High

    Identification of USP8 as an active ubiquitin isopeptidase required for S-phase entry established it as a functionally important DUB linking ubiquitin homeostasis to cell proliferation.

    Evidence In vitro ubiquitin cleavage assay with recombinant and immunoprecipitated USP8; antisense microinjection blocking S-phase in fibroblasts

    PMID:9628861

    Open questions at the time
    • Physiological substrates unidentified
    • Mechanism linking DUB activity to S-phase progression unknown
  2. 2000 High

    Discovery that USP8 binds the SH3 domain of STAM via RXXK motifs placed USP8 in the ESCRT-0/endosomal sorting machinery, providing a recruitment mechanism.

    Evidence Far-Western screening and systematic mutagenesis of PX(V/I)(D/N)RXXKP motifs

    PMID:10982817

    Open questions at the time
    • Whether STAM binding is required for USP8 endosomal function untested
    • Endosomal substrates unidentified
  3. 2005 High

    Demonstration that USP8 directly deubiquitinates EGFR on endosomes and that its depletion accelerates EGFR lysosomal degradation established USP8 as a key regulator of receptor tyrosine kinase downregulation.

    Evidence In vitro deubiquitination of EGFR by immunopurified USP8; RNAi knockdown causing EGFR hyperubiquitination and accelerated degradation

    PMID:16120644 PMID:16520378

    Open questions at the time
    • Structural basis of EGFR recognition unknown
    • Relative contribution of USP8 versus other endosomal DUBs unclear
  4. 2006 High

    Crystal structures of three USP8 domains revealed a domain-swapped N-terminal homodimer, the rhodanese–Nrdp1 interface, and a closed catalytic domain conformation, providing the first structural framework for understanding USP8 regulation and substrate engagement.

    Evidence X-ray crystallography of N-terminal, rhodanese, and catalytic domains

    PMID:17035239

    Open questions at the time
    • Full-length structure unavailable
    • Mechanism of catalytic domain opening upon substrate engagement unresolved
  5. 2007 High

    Identification of phospho-Ser680-dependent 14-3-3 binding as an inhibitory switch relieved during mitosis, and the MIT domain as an endosomal targeting module via CHMP interactions, defined two major regulatory axes controlling USP8 activity and localization.

    Evidence Co-IP/mass spec identifying 14-3-3 partners; phospho-specific antibodies; in vitro activity inhibition by 14-3-3; MIT domain deletion failing to rescue EGFR degradation or STAM stability

    PMID:17711858 PMID:17720156

    Open questions at the time
    • Kinase(s) and phosphatase(s) regulating Ser680 phosphorylation not identified
    • Whether 14-3-3 binding alters USP8 localization untested
  6. 2012 High

    Extension of USP8 function beyond receptor trafficking: USP8 deubiquitinates Smoothened to promote Hedgehog signaling and deubiquitinates CLOCK to regulate circadian transcription in Drosophila, revealing conserved roles in developmental and circadian pathways.

    Evidence Drosophila RNAi screen and in vivo ubiquitination assays for Smo; genetic loss-of-function with CLK ubiquitylation cycling and locomotor rhythm analysis for CLOCK

    PMID:22253573 PMID:23154984

    Open questions at the time
    • Whether mammalian USP8 regulates Smoothened or CLOCK orthologs untested
    • Whether these substrates are deubiquitinated on endosomes or elsewhere unclear
  7. 2013 High

    HD-PTP was shown to recruit USP8 to EGFR at ESCRT-0, competing with STAM2 binding and coordinating the handoff from ESCRT-0 to ESCRT-III, providing a detailed mechanistic model of USP8-dependent MVB sorting.

    Evidence Co-IP, binding competition assays, siRNA epistasis, and ILV sorting assays

    PMID:23477725

    Open questions at the time
    • Structural basis of the HD-PTP/USP8/CHMP4B ternary complex unresolved
    • Whether this handoff mechanism applies to non-EGFR cargoes unknown
  8. 2014 High

    Discovery that USP8 removes K6-linked ubiquitin chains from parkin to promote mitophagy, and that somatic USP8 mutations in the 14-3-3 binding motif cause Cushing's disease by sustaining EGFR-POMC signaling, linked USP8 to mitochondrial quality control and a defined human disease.

    Evidence K6-linkage-specific ubiquitin analysis with parkin translocation/mitophagy assays; exome sequencing of corticotroph adenomas with in vitro activity and POMC reporter assays

    PMID:25216678 PMID:25485838

    Open questions at the time
    • How parkin K6-ubiquitin chain removal mechanistically facilitates mitochondrial recruitment unresolved
    • Whether Cushing's mutations affect substrates beyond EGFR unknown
  9. 2018 High

    EGFR-dependent Tyr717/Tyr810 phosphorylation was shown to activate USP8, which stabilizes trichoplein to suppress ciliogenesis; the 14-3-3ζ/USP8-pSer718 crystal structure provided atomic-level understanding of the inhibitory mechanism disrupted in Cushing's disease.

    Evidence In vitro kinase assay, phosphosite mutagenesis, ciliogenesis assays, zebrafish KO; crystal structure of 14-3-3ζ/pSer718 peptide complex with biophysical binding measurements

    PMID:29472535 PMID:29473952

    Open questions at the time
    • How tyrosine phosphorylation structurally activates the catalytic domain unknown
    • Whether phosphorylation events are coordinated in a single activation cascade unclear
  10. 2019 High

    USP8 was established as a regulator of autophagy through deubiquitination of SQSTM1/p62 (K11-linked chains at K420) and EPG5 (K63-linked chains at K252), demonstrating linkage-specific substrate selectivity in controlling autophagic flux and stemness.

    Evidence In vitro deubiquitination with linkage-specific analysis, K-to-R mutant rescue, autophagy flux assays, ESC differentiation

    PMID:30931944 PMID:31241013

    Open questions at the time
    • Structural basis of USP8 linkage selectivity (K6, K11, K27, K48, K63) not determined
    • Whether autophagy regulation is endosome-dependent or cytosolic unclear
  11. 2022 High

    USP8 was found to regulate immune checkpoints and cell division: its inhibition elevates PD-L1 and MHC-I via TRAF6-mediated K63 ubiquitination and NF-κB, while in Drosophila germline USP8 deubiquitinates ESCRT-III/CHMP4 to control abscission bridge completion.

    Evidence Linkage-specific ubiquitination assays, NF-κB/MHC-I reporters, in vivo tumor models for PD-L1; Drosophila USP8 KO/overexpression with ubiquitination-resistant CHMP4 mutant and live abscission imaging

    PMID:35361799 PMID:35587967

    Open questions at the time
    • Direct PD-L1 deubiquitination by USP8 not demonstrated (indirect via TRAF6 K63 chains)
    • Whether abscission regulation is conserved in mammalian cells untested
  12. 2024 High

    USP8 was shown to stabilize GPX4 to protect against ferroptosis and to deubiquitinate K27-linked chains on DDX3X to promote cGAS-STING innate immune signaling via phase separation, extending USP8 function to ferroptosis defense and cytosolic nucleic acid sensing.

    Evidence In vitro deubiquitination of GPX4, conditional Usp8 intestinal KO mice with lipid peroxidation phenotype; K27-linkage-specific DDX3X deubiquitination, LLPS condensate assays, Trex1−/− mouse model

    PMID:38598341 PMID:38795350

    Open questions at the time
    • Whether GPX4 stabilization is endosome-dependent or occurs in cytosol unknown
    • Structural basis of K27-linkage specificity for DDX3X not determined

Open questions

Synthesis pass · forward-looking unresolved questions
  • A unified structural and regulatory model explaining how USP8 achieves selectivity among its many substrates and ubiquitin chain types, and whether its diverse functions are coordinated or independently regulated, remains to be established.
  • No full-length USP8 structure available
  • Structural basis of broad yet linkage-specific chain processing (K6, K11, K27, K48, K63) unresolved
  • Whether substrate selection is primarily determined by localization (endosomal vs. cytosolic) or by intrinsic catalytic preferences is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016787 hydrolase activity 3
Localization
GO:0005768 endosome 7 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-5653656 Vesicle-mediated transport 5 R-HSA-392499 Metabolism of proteins 4 R-HSA-168256 Immune System 3 R-HSA-9612973 Autophagy 3 R-HSA-1640170 Cell Cycle 2 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-1643685 Disease 1
Partners
14-3-3CHMP1BCLEC16AEGFRHD-PTPNRDP1PRKNSTAM
Complex memberships
Clec16a-Nrdp1-USP8 mitophagy complexESCRT-0 (STAM/Hrs)-associatedUSP8-CHMP1B-IST1 complex

Evidence

Reading pass · 50 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; its catalytic activity was demonstrated both as a recombinant protein and after immunoprecipitation from cell extracts, and reducing its abundance by antisense microinjection prevents fibroblast entry into S-phase. In vitro ubiquitin cleavage assay with recombinant/immunoprecipitated protein; antisense plasmid microinjection; catalytic-site mutant overexpression The EMBO journal High 9628861
2000 USP8/UBPY binds the SH3 domain of Hrs-binding protein (STAM) via a novel non-canonical motif PX(V/I)(D/N)RXXKP; two such motifs were identified by mutagenic analysis. Far-Western screening, mutagenic analysis of binding motif The Journal of biological chemistry High 10982817
2001 Mouse USP8 (mUBPy) interacts with the Ras GEF CDC25(Mm)/Ras-GRF1 via the N-terminal domain of CDC25(Mm), deubiquitinates it in co-transfected cells, and extends its half-life. Yeast two-hybrid, GST pulldown, co-immunoprecipitation, co-transfection ubiquitination assay, pulse-chase half-life experiment The Journal of biological chemistry High 11500497
2004 USP8 physically interacts with the E3 ubiquitin ligase Nrdp1 via its rhodanese and catalytic domains, deubiquitinates Nrdp1, and markedly stabilizes it; a catalytically inactive USP8 point mutant destabilizes endogenous Nrdp1. Affinity chromatography, co-immunoprecipitation, transfection with catalytic mutant, protein stability assay Molecular and cellular biology High 15314180
2005 USP8/UBPY deubiquitinates EGFR on endosomes; immunopurified UBPY deubiquitinates EGFR in vitro; catalytically inactive UBPY accumulates on endosomes overlapping with EGFR; RNAi-mediated UBPY depletion elevates EGFR ubiquitination and accelerates its lysosomal degradation. In vitro deubiquitination assay with immunopurified protein, RNAi knockdown, catalytic-mutant localization, EGF-stimulated degradation assay Molecular biology of the cell High 16120644
2006 USP8/UBPY processes Lys-48- and Lys-63-linked polyubiquitin in vitro and deubiquitinates mono-ubiquitinated receptor tyrosine kinases; UBPY depletion by siRNA causes global accumulation of ubiquitinated proteins on endosomes, enlarged multivesicular endosomal structures, and strongly inhibits degradation of EGFR and Met; UBPY binding partner STAM is destabilized upon UBPY knockdown. In vitro ubiquitin chain processing assay, siRNA knockdown, electron microscopy, receptor degradation assay The Journal of biological chemistry High 16520378
2006 Catalytically inactive UBPY or UBPY depletion causes accumulation of ubiquitinated proteins and Eps15 on morphologically aberrant multivesicular endosomes; USP8 directly deubiquitinates Eps15 in vitro. Catalytic-mutant overexpression, RNAi, in vitro deubiquitination assay, electron microscopy Traffic High 16771824
2006 Crystal structures of USP8 reveal: (i) N-terminal domain forms a novel homodimer via domain-swapped five-helix bundles; (ii) rhodanese domain binds Nrdp1 via a conserved loop—structure of rhodanese–Nrdp1 complex determined; (iii) catalytic domain adopts a closed, substrate-incompatible conformation with a zinc ribbon subdomain near the ubiquitin-binding site. X-ray crystallography of three separate USP8 domain structures The Journal of biological chemistry High 17035239
2006 UBPY/USP8 constitutively co-precipitates with EGFR in a bivalent manner and is a substrate for Src-family tyrosine kinases activated downstream of EGFR; dominant-negative UBPY mutants alter EGFR ubiquitination, expression levels, and MAPK signaling. Co-immunoprecipitation, dominant-negative mutant overexpression, kinase activity assay The Journal of biological chemistry High 17121848
2007 USP8 contains an N-terminal MIT domain that interacts with CHMP proteins (preferentially CHMP7 and CHMP1A/B) and is required for endosomal localization; MIT-deleted USP8 cannot rescue STAM stability or reverse the block to EGFR degradation; STAM stimulates USP8 deubiquitinase activity. Domain deletion mutagenesis, binding assays with CHMP family members, siRNA rescue experiments, STAM stability 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 motif RSYS680SP; 14-3-3 binding inhibits USP8 isopeptidase activity toward polyubiquitin and EGFR in vitro and in vivo; during M phase, USP8 is dephosphorylated at Ser680, dissociates from 14-3-3, and its activity is enhanced. Co-immunoprecipitation/mass spectrometry, phosphatase treatment, 32P metabolic labeling, phospho-specific antibody, in vitro activity assay with recombinant 14-3-3, cell cycle fractionation Experimental cell research High 17720156
2010 USP8 forms a complex with STAM via RXXK motifs and protects EGFR from lysosomal degradation by deubiquitinating it on early endosomes in an Hrs-dependent pathway; catalytic inactivation of USP8 causes EGFR hyperubiquitination and accumulation on high-ubiquitin endosomes. siRNA depletion, catalytic-mutant analysis, epistasis with Hrs siRNA, endosomal ubiquitin dynamics assay The Journal of biological chemistry High 20736164
2010 USP8 depletion stabilizes CXCR4 on the cell surface and attenuates its degradation without affecting its ubiquitination, by perturbing ESCRT-0 ubiquitination; USP8 functionally opposes the ubiquitin ligase AIP4 at the sorting endosome. siRNA knockdown, receptor trafficking assay, ESCRT-0 ubiquitination analysis, epistasis with AIP4 The Journal of biological chemistry High 20876529
2010 ERBB2 is a target for USP8-mediated deubiquitination; catalytically inactive Usp8-C748A enhances EGFR-ErbB2 ubiquitination and USP8 is tyrosine-phosphorylated upon EGFR-ErbB2 activation in a Src- and EGFR-kinase–dependent manner. Co-immunoprecipitation, catalytic-mutant overexpression, tyrosine phosphorylation assay Cellular signalling Medium 21044682
2011 USP8 interacts with KCa3.1 channel after endocytosis (DUB Chip microarray and co-immunoprecipitation); wild-type USP8 overexpression accelerates channel deubiquitylation, while catalytically inactive USP8 or siRNA knockdown enhances ubiquitylated KCa3.1 and inhibits its lysosomal degradation. DUB Chip protein microarray, co-immunoprecipitation, USP8 overexpression/knockdown, BLAP-tagging/TUBE assay FASEB journal High 21828287
2012 USP8 deubiquitinates Smoothened (Smo) in Drosophila Hh signaling; RNAi inactivation of USP8 increases Smo ubiquitination and attenuates Hh-induced Smo cell-surface accumulation; USP8 overexpression prevents Smo ubiquitination and promotes its cell-surface localization; Hh promotes USP8-Smo interaction via Smo residues 625–753. In vivo RNAi screen, co-immunoprecipitation, ubiquitination assay, cell-surface localization imaging PLoS biology High 22253573
2012 In Drosophila, USP8 deubiquitylates CLOCK protein; usp8 loss-of-function enhances CLK/CYC transcriptional activity; CLK ubiquitylation cycles in vivo and peaks with maximal transcription; USP8-DN increases CLK ubiquitylation and ablates molecular clock oscillations in circadian neurons. Drosophila RNAi/dominant-negative genetics, CLK ubiquitylation cycling assay, locomotor rhythm analysis, circadian neuron imaging Genes & development High 23154984
2013 HD-PTP recruits UBPY/USP8 to EGFR at ESCRT-0; USP8 interacts with HD-PTP-bound CHMP4B and competes with HD-PTP for STAM2 SH3 binding; this concerted recruitment deubiquitinates EGFR and transfers it from ESCRT-0 to ESCRT-III for MVB sorting. Co-immunoprecipitation, binding competition assays, siRNA epistasis, EGFR sorting assay to intralumenal vesicles Current biology High 23477725
2013 USP8 regulates ENaC ubiquitination and trafficking: USP8 co-immunoprecipitates with ENaC, deubiquitinates it, and redirects its endocytic sorting away from degradation toward the cell surface; mutation of ENaC cytoplasmic lysines reduces USP8 effect, confirming deubiquitination dependence. Co-immunoprecipitation, Xenopus oocyte electrophysiology, HEK293 surface abundance assay, lysine-mutant ENaC The Journal of biological chemistry High 23297398
2013 RNF41 ubiquitylates and reduces levels of USP8; loss of USP8 explains RNF41-mediated effects on cytokine receptor (leptin, LIF) trafficking; USP8 in turn stabilizes RNF41 (reciprocal cross-regulation); RNF41 indirectly destabilizes the ESCRT-0 complex through suppression of USP8. Co-immunoprecipitation, siRNA knockdown, receptor trafficking assays, ESCRT-0 stability assay Journal of cell science High 23750007
2013 USP8 depletion reduces BACE1 levels, increases BACE1 ubiquitination at K501, and promotes BACE1 accumulation in early/late endosomes while depleting recycling endosome pools; decreased BACE1 reduces amyloid-β production. RNAi knockdown, ubiquitination assay, subcellular fractionation/immunofluorescence, amyloid-β ELISA The Journal of biological chemistry High 27302062
2013 HIF1α is a USP8 substrate; USP8 counteracts pVHL-mediated HIF1α ubiquitination to maintain basal HIF1α levels and HIF transcriptional output in normoxia, which is required for Rabaptin5 repression and ciliogenesis. siRNA screen, HIF1α deubiquitination assay, ciliogenesis assay, epistasis with pVHL EMBO reports High 24378640
2014 USP8 depletion redistributes the cation-independent mannose-6-phosphate receptor (ci-M6PR) from the TGN to endosomes via a retromer-dependent mechanism, causes secretion of unprocessed Cathepsin D, and this requires USP8 catalytic activity and its MIT domain for endosomal localization. siRNA depletion, siRNA-resistant rescue, catalytic and MIT-domain mutants, Cathepsin D processing assay, immunofluorescence Traffic High 24894536
2014 USP8 preferentially removes non-canonical K6-linked ubiquitin chains from parkin; this deubiquitination is required for efficient parkin recruitment to depolarized mitochondria and subsequent mitophagy. Co-immunoprecipitation, linkage-specific ubiquitin chain assay, mitophagy assay (parkin translocation), siRNA knockdown The EMBO journal High 25216678
2014 Somatic mutations in USP8 cluster in the 14-3-3 protein binding motif, enhance proteolytic cleavage and catalytic activity of USP8, lead to increased EGFR deubiquitination impairing its downregulation, sustain EGF signaling, and enhance POMC promoter activity in corticotroph adenomas causing Cushing's disease. Exome sequencing, in vitro catalytic activity assay with mutant USP8, EGFR ubiquitination assay, POMC promoter reporter assay Nature genetics High 25485838
2014 USP8 deubiquitinates LRIG1, and SAIT301 antibody triggers Met degradation by inhibiting the LRIG1–USP8 interaction, leading to LRIG1 ubiquitination and lysosomal delivery of the LRIG1–Met complex. Co-immunoprecipitation, ubiquitination assay, antibody-induced interaction disruption, receptor degradation assay Scientific reports Medium 24828152
2014 USP8 deubiquitinates AMPA receptors (AMPARs); NMDAR activation causes dephosphorylation and activation of USP8, which deubiquitinates AMPARs opposing Nedd4-1-mediated ubiquitination; USP8 and Nedd4-1 inversely regulate surface AMPAR levels and synaptic strength in hippocampal neurons. Surface receptor assay, electrophysiology, siRNA knockdown, phosphorylation assay, homeostatic scaling model The Journal of neuroscience High 25505317
2015 BRUCE acts as a scaffold bridging USP8 and BRIT1; USP8 catalyzes deubiquitination of K63-linked ubiquitin on BRIT1, which is a prerequisite for BRIT1 recruitment to DNA double-strand break (DSB) sites by γ-H2AX; loss of BRUCE or USP8 impairs BRIT1 deubiquitination, DSB focus formation, chromatin relaxation, and homologous recombination repair. Co-immunoprecipitation, in vitro deubiquitination assay, linkage-specific ubiquitin analysis, DNA damage foci assay, HR repair assay Proceedings of the National Academy of Sciences of the United States of America High 25733871
2015 USP8 is a critical T cell immunomodulatory deubiquitinase: it interacts with the TCR adaptor Gads and with 14-3-3β; caspase-dependent processing of USP8 occurs after TCR stimulation; T cell-specific USP8 deletion in mice impairs thymocyte maturation and Foxo1-mediated IL-7Rα upregulation, leading to colitis from disturbed T cell homeostasis. T cell-specific conditional knockout mice, co-immunoprecipitation with TCR components, thymocyte maturation assay, caspase cleavage assay Nature immunology High 26214742
2016 USP8 deubiquitinates K63-linked ubiquitin chains on α-synuclein in cells and after purification; Usp8 knockdown in Drosophila dopaminergic neurons reduces α-synuclein levels and α-synuclein-induced toxicity; in human cells, Usp8 knockdown increases lysosomal degradation of α-synuclein. Co-immunoprecipitation, in vitro/in-cell deubiquitination assay, Drosophila RNAi, lysosomal degradation assay Proceedings of the National Academy of Sciences of the United States of America High 27444016
2016 USP8 directly deubiquitinates and stabilizes FLIPL (but not FLIPs); USP8 depletion induces FLIPL destabilization, promoting death receptor–mediated (Fas, TRAIL, TNFα) extrinsic apoptosis via enhanced DISC or TNFR1 complex II formation. Co-immunoprecipitation, in vitro deubiquitination assay, siRNA knockdown, apoptosis assay, xenograft model Oncogene High 27321185
2017 Clec16a, Nrdp1, and USP8 form a ubiquitin-dependent tripartite mitophagy regulatory complex in pancreatic β-cells; Clec16a functions as an E3 ligase promoting non-degradative ubiquitin conjugates to stabilize the complex; disruption of this complex impairs β-cell mitophagy, oxygen consumption, and insulin secretion. Co-immunoprecipitation, E3 ligase assay for Clec16a, mitophagy assay, β-cell oxygen consumption, insulin secretion assay Diabetes High 29180353
2018 EGFR kinase directly phosphorylates USP8 on Tyr-717 and Tyr-810, elevating its deubiquitinase activity, which stabilizes trichoplein and thereby maintains Aurora A activity to suppress ciliogenesis in dividing cells. In vitro kinase assay, site-directed mutagenesis of phosphorylation sites, ciliogenesis assay, trichoplein stability assay, usp8 knockout zebrafish phenotype Nature communications High 29472535
2018 Crystal structure of 14-3-3ζ in complex with the USP8 pSer718-containing peptide reveals the structural basis of the 14-3-3/USP8 interaction; Cushing's disease mutations in this motif reduce 14-3-3 binding affinity as quantified by fluorescence polarization and isothermal titration calorimetry. X-ray crystallography, fluorescence polarization, isothermal titration calorimetry FEBS letters High 29473952
2018 USP8 deubiquitinates CHMP1B within its flexible loop; CHMP1B ubiquitination is required for its function in EGFR trafficking and Drosophila wing development; USP8 deubiquitinates CHMP1B and is found with CHMP1B in a ~500 kDa complex with IST1. Co-immunoprecipitation, in vitro deubiquitination assay, size-exclusion chromatography, Drosophila genetics PLoS genetics High 29933386
2018 USP8 deubiquitinates and stabilizes Connexin-43 (Cx43): USP8 reduces both mono- and poly-ubiquitination of Cx43, preventing autophagy-mediated degradation; USP8 knockdown decreases Cx43 levels and suppresses intercellular dye transfer. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, dye transfer assay The Journal of biological chemistry Medium 29626091
2018 USP8 deubiquitinates SHANK3 (and SHANK1), preventing proteasomal degradation; USP8 overexpression in primary rat neurons increases SHANK3/SHANK1 protein levels and dendritic spine density; USP8 is essential for activity-dependent changes in SHANK3 protein levels. Co-immunoprecipitation, ubiquitination assay, neuronal overexpression/knockdown, dendritic spine imaging The Journal of neuroscience High 29735556
2018 USP8 regulates VEGFR2 deubiquitination, trafficking, and proteolysis; USP8 depletion alters VEGFR2 ubiquitination, causes its accumulation in the endosome-lysosome system producing a unique extracellular domain fragment, and impairs VEGF-A-stimulated signaling. siRNA knockdown, VEGFR2 ubiquitination assay, endosomal accumulation assay, signaling phosphorylation assay Traffic Medium 26459808
2019 USP8 directly interacts with and deubiquitinates SQSTM1/p62, preferentially removing K11-linked chains at K420 within the UBA domain; this inhibits p62 degradation and autophagic flux; K420R mutant p62 is unresponsive to USP8. Co-immunoprecipitation, in vitro deubiquitination assay with linkage-specific analysis, K420R mutant rescue, autophagic flux assay Autophagy High 31241013
2019 USP8 deubiquitinates EPG5, removing K63-linked chains at K252, enhancing EPG5 interaction with LC3 and autophagic flux; this maintains ESC stemness. Co-immunoprecipitation, in vitro deubiquitination assay, LC3 interaction assay, ESC differentiation assay Nature communications High 30931944
2019 USP8 deubiquitinates the leptin receptor (LepRb), stabilizes it at the cell surface, and is required for leptin-stimulated synaptogenesis in hippocampal neurons; leptin stimulates USP8 activity and gene expression via CREB-dependent transcription; USP8 in complex with LepRb. Co-immunoprecipitation, surface receptor assay, USP8 activity assay, dominant-negative CREB, shRNA knockdown, synaptogenesis assay Endocrinology High 31199479
2020 H2S promotes S-sulfhydration of USP8, a post-translational modification that enhances USP8 deubiquitinase activity toward parkin; sulfhydration-enhanced USP8 promotes parkin recruitment to mitochondria and mitophagy in diabetic cardiomyocytes. S-sulfhydration assay, dithiothreitol reversal, co-immunoprecipitation of USP8 with parkin, mitophagy assay in cardiomyocytes Aging and disease Medium 32257541
2021 USP8 deubiquitinates and stabilizes TAK1 by removing K63-linked ubiquitin; reduced USP8 expression in macrophages (via METTL3/MALAT1/PTBP1 axis) leads to increased TAK1 ubiquitination and protein instability, promoting pyroptosis and M1 polarization. Co-immunoprecipitation, protein degradation assay, ubiquitination assay, RNA pull-down/RIP for upstream regulation Cell death discovery Medium 34839365
2022 USP8 inhibition increases TRAF6-mediated K63-linked ubiquitination of PD-L1, antagonizing its K48-linked degradation and elevating PD-L1 protein abundance; USP8 inhibition also activates NF-κB signaling and MHC-I expression, enhancing anti-tumor immunity. siRNA knockdown, ubiquitination linkage assay, NF-κB reporter assay, MHC-I expression assay, in vivo tumor models Nature communications High 35361799
2022 USP8 directly deubiquitinates and stabilizes TβRII (type II TGF-β receptor), increasing its plasma membrane and extracellular vesicle expression; USP8 promotes TGF-β/SMAD-driven EMT and metastasis, and enables TβRII+ EVs to induce CD8+ T cell exhaustion. Co-immunoprecipitation, in vitro deubiquitination assay, surface biotinylation, EV characterization, EMT/invasion assay, in vivo metastasis model The EMBO journal High 35811497
2022 USP8 deubiquitinase targets ESCRT-III proteins CHMP2B and Shrub/CHMP4 in Drosophila; USP8 loss converts incomplete germline cell divisions into complete divisions; USP8 overexpression does the reverse; a Shrub/CHMP4 ubiquitination-resistant variant fails to localize to abscission bridges and cannot complete abscission. Drosophila genetics (USP8 KO and overexpression), ESCRT-III ubiquitination-resistant mutant analysis, live imaging of abscission bridges Science High 35587967
2023 USP8 stabilizes O-GlcNAc transferase (OGT) by inhibiting K48-linked poly-ubiquitination at K117 of OGT; SLK-mediated phosphorylation of USP8 at S716 is required for the USP8–OGT interaction; OGT O-GlcNAcylates SLC7A11 at Ser26 to support cystine import and ferroptosis resistance. Co-immunoprecipitation, in vitro deubiquitination assay, site-directed mutagenesis (K117R OGT, S716 USP8), O-GlcNAcylation assay, cystine import assay Advanced science High 37867237
2023 USP8 deubiquitinates and stabilizes β-catenin by inhibiting K48-linked poly-ubiquitination; the USP domain of USP8 interacts with the ARM domain of β-catenin; USP8 depletion reduces β-catenin levels and Wnt target gene expression. Co-immunoprecipitation, ubiquitination assay (K48-linkage specific), domain interaction mapping, TOP-flash reporter assay Cell death & disease Medium 37311739
2024 USP8 directly interacts with and deubiquitinates GPX4, stabilizing it and protecting against ferroptosis; homozygous intestinal epithelial cell Usp8 deletion in mice causes lipid peroxidation and increased IEC death; USP8 inhibition destabilizes GPX4 and sensitizes cancer cells to ferroptosis. Co-immunoprecipitation, in vitro deubiquitination assay, conditional Usp8 KO mice, lipid peroxidation assay, ferroptosis assay Proceedings of the National Academy of Sciences of the United States of America High 38598341
2024 USP8 localizes to stress granules upon dsDNA stimulation and deubiquitinates K27-linked chains from the intrinsically disordered region of DDX3X, enhancing DDX3X LLPS condensation, cGAS phase separation, and downstream STING-mediated interferon signaling. Co-immunoprecipitation, K27-linkage-specific deubiquitination assay, stress granule imaging, LLPS/condensate assay, Trex1-/- mouse model Cell reports High 38795350

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 427 25485838
2014 USP8 regulates mitophagy by removing K6-linked ubiquitin conjugates from parkin. The EMBO journal 320 25216678
2015 Recurrent gain-of-function USP8 mutations in Cushing's disease. Cell research 259 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
2004 Stabilization of the E3 ubiquitin ligase Nrdp1 by the deubiquitinating enzyme USP8. Molecular and cellular biology 134 15314180
2006 Amino-terminal dimerization, NRDP1-rhodanese interaction, and inhibited catalytic domain conformation of the ubiquitin-specific protease 8 (USP8). The Journal of biological chemistry 133 17035239
2021 The METTL3/MALAT1/PTBP1/USP8/TAK1 axis promotes pyroptosis and M1 polarization of macrophages and contributes to liver fibrosis. Cell death discovery 124 34839365
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 118 26578638
2022 USP8 inhibition reshapes an inflamed tumor microenvironment that potentiates the immunotherapy. Nature communications 116 35361799
2012 USP8 promotes smoothened signaling by preventing its ubiquitination and changing its subcellular localization. PLoS biology 116 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 109 27444016
2024 USP8-governed GPX4 homeostasis orchestrates ferroptosis and cancer immunotherapy. Proceedings of the National Academy of Sciences of the United States of America 104 38598341
2006 A deubiquitinating enzyme UBPY regulates the level of protein ubiquitination on endosomes. Traffic (Copenhagen, Denmark) 100 16771824
2023 Targeting USP8 Inhibits O-GlcNAcylation of SLC7A11 to Promote Ferroptosis of Hepatocellular Carcinoma via Stabilization of OGT. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 97 37867237
2013 Recruitment of UBPY and ESCRT exchange drive HD-PTP-dependent sorting of EGFR to the MVB. Current biology : CB 95 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 86 31241013
2019 Driver mutations in USP8 wild-type Cushing's disease. Neuro-oncology 84 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 80 11500497
2022 USP8 promotes cancer progression and extracellular vesicle-mediated CD8+ T cell exhaustion by deubiquitinating the TGF-β receptor TβRII. The EMBO journal 76 35811497
2017 Somatic USP8 Gene Mutations Are a Common Cause of Pediatric Cushing Disease. The Journal of clinical endocrinology and metabolism 76 28505279
2020 Exogenous H2S Promoted USP8 Sulfhydration to Regulate Mitophagy in the Hearts of db/db Mice. Aging and disease 73 32257541
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 71 25505317
2023 USP8 positively regulates hepatocellular carcinoma tumorigenesis and confers ferroptosis resistance through β-catenin stabilization. Cell death & disease 70 37311739
2015 The ubiquitin-specific protease USP8 is critical for the development and homeostasis of T cells. Nature immunology 69 26214742
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 62 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 61 35658874
2016 The Endosome-associated Deubiquitinating Enzyme USP8 Regulates BACE1 Enzyme Ubiquitination and Degradation. The Journal of biological chemistry 61 27302062
2018 EGF receptor kinase suppresses ciliogenesis through activation of USP8 deubiquitinase. Nature communications 60 29472535
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 51 31845722
2016 USP8 suppresses death receptor-mediated apoptosis by enhancing FLIPL stability. Oncogene 49 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 48 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 47 33221858
2021 The oncogenic role of ubiquitin specific peptidase (USP8) and its signaling pathways targeting for cancer therapeutics. Archives of biochemistry and biophysics 45 33600786
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 44 32335193
2018 Clinical characteristics and surgical outcome in USP8-mutated human adrenocorticotropic hormone-secreting pituitary adenomas. Endocrine 44 30315484
2013 Reciprocal cross-regulation between RNF41 and USP8 controls cytokine receptor sorting and processing. Journal of cell science 44 23750007
2019 Germline USP8 Mutation Associated With Pediatric Cushing Disease and Other Clinical Features: A New Syndrome. The Journal of clinical endocrinology and metabolism 43 31162547
2018 USP8 Mutations in Pituitary Cushing Adenomas-Targeted Analysis by Next-Generation Sequencing. Journal of the Endocrine Society 42 29600293
2019 USP8 maintains embryonic stem cell stemness via deubiquitination of EPG5. Nature communications 41 30931944
2017 Somatic USP8 mutations are frequent events in corticotroph tumor progression causing Nelson's tumor. European journal of endocrinology 41 28982703
2015 USP8 and PARK2/parkin-mediated mitophagy. Autophagy 41 25700639
2010 ERBB2 is a target for USP8-mediated deubiquitination. Cellular signalling 40 21044682
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 39 25733871
2012 CLOCK deubiquitylation by USP8 inhibits CLK/CYC transcription in Drosophila. Genes & development 39 23154984
2020 SST5 expression and USP8 mutation in functioning and silent corticotroph pituitary tumors. Endocrine connections 38 32101529
2019 Cushing's disease due to somatic USP8 mutations: a systematic review and meta-analysis. Pituitary 38 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
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
2015 Decoding the genetic basis of Cushing's disease: USP8 in the spotlight. European journal of endocrinology 35 26012588
2019 Impact of USP8 Gene Mutations on Protein Deregulation in Cushing Disease. The Journal of clinical endocrinology and metabolism 34 30844069
2022 The deubiquitinase USP8 targets ESCRT-III to promote incomplete cell division. Science (New York, N.Y.) 33 35587967
2018 Biophysical and structural insight into the USP8/14-3-3 interaction. FEBS letters 32 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 32 29735556
2015 VEGFR2 Trafficking, Signaling and Proteolysis is Regulated by the Ubiquitin Isopeptidase USP8. Traffic (Copenhagen, Denmark) 32 26459808
2022 Improved pasireotide response in USP8 mutant corticotroph tumours in vitro. Endocrine-related cancer 30 35686696
2021 Inhibiting USP8 overcomes hepatocellular carcinoma resistance via suppressing receptor tyrosine kinases. Aging 29 34081623
2024 Stress granule-localized USP8 potentiates cGAS-mediated type I interferonopathies through deubiquitination of DDX3X. Cell reports 28 38795350
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
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 USP8 regulates liver cancer progression via the inhibition of TRAF6-mediated signal for NF-κB activation and autophagy induction by TLR4. Translational oncology 22 34688043
2022 Discovery of Potent Small-Molecule USP8 Inhibitors for the Treatment of Breast Cancer through Regulating ERα Expression. Journal of medicinal chemistry 21 35786929
2021 Genetic Profiling of a Cohort of Italian Patients with ACTH-Secreting Pituitary Tumors and Characterization of a Novel USP8 Gene Variant. Cancers 21 34439178
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
2021 USP8, USP48, and BRAF mutations differ in their genotype-phenotype correlation in Asian Indian patients with Cushing's disease. Endocrine 20 34664215
2020 Down-regulation of USP8 Inhibits Cholangiocarcinoma Cell Proliferation and Invasion. Cancer management and research 20 32273758
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
2021 USP8 inhibitor RA-9 reduces ACTH release and cell growth in tumor corticotrophs. Endocrine-related cancer 19 34086599
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
2019 USP8 ameliorates cognitive and motor impairments via microglial inhibition in a mouse model of sepsis-associated encephalopathy. Brain research 18 31075263
2015 The Deubiquitinating Enzyme UBPY Is Required for Lysosomal Biogenesis and Productive Autophagy in Drosophila. PloS one 18 26571504
2023 Expanding the spectrum of tyrosine kinase fusions in calcified chondroid mesenchymal neoplasms: Identification of a novel PDGFRA::USP8 gene fusion. Genes, chromosomes & cancer 17 37642440
2020 Knockdown of USP8 Inhibits the Growth of Lung Cancer Cells. Cancer management and research 17 33293867
2018 Effect of deubiquitinase USP8 on hypoxia/reoxygenation‑induced inflammation by deubiquitination of TAK1 in renal tubular epithelial cells. International journal of molecular medicine 17 30221684
2013 The Usp8 deubiquitination enzyme is post-translationally modified by tyrosine and serine phosphorylation. Cellular signalling 17 23333852
2022 Responsiveness to DDAVP in Cushing's disease is associated with USP8 mutations through enhancing AVPR1B promoter activity. Pituitary 16 35451730
2021 USP8 is a Novel Therapeutic Target in Melanoma Through Regulating Receptor Tyrosine Kinase Levels. Cancer management and research 16 34079371