USP25 (ubiquitin carboxyl-terminal hydrolase 25; historically called "USP on chromosome 21" / USP21) is a cytoplasmic cysteine (papain-like, peptidase C19 family) deubiquitinating enzyme. It has an N-terminal UBA-like domain and tandem ubiquitin-interacting motifs (UIM) that recognize ubiquitin, a catalytic USP domain (active-site Cys-178), and a C-terminal region that mediates oligomerization, with an inhibited homotetramer and an active homodimer state controlling catalytic output. USP25 hydrolyzes ubiquitin from substrates and can cleave both K48- and K63-linked polyubiquitin chains, thereby protecting specific substrates from proteasomal degradation and modulating signaling. Characterized substrates and pathways include stabilization of the tankyrases TNKS1/TNKS2 to modulate Wnt/beta-catenin signaling, deubiquitination and stabilization of KEAP1 within the KEAP1-NRF2 oxidative-stress axis, removal of K63-linked ubiquitin from TRAF5/TRAF6 to restrain interleukin-17 signaling and inflammation, stabilization of TRAF3 and ERLIN1/2 in innate antiviral responses, and rescue of ERAD substrates by counteracting the HRD1 ubiquitin ligase. Its activity is regulated by sumoylation at Lys-99 (which impairs ubiquitin binding), by SMURF1-mediated K48 ubiquitination targeting it for degradation, by SYK phosphorylation, and by its oligomeric state. A muscle-specific isoform (USP25m) is induced during myocyte differentiation and interacts with sarcomeric proteins (ACTA1, FLNC, MYBPC1). Heterozygous USP25 variants cause idiopathic generalized epilepsy (EIG19).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0032183 SUMO binding | IBA GO_REF:0000033 | ACCEPT | Summary: USP25 binds SUMO via an N-terminal SUMO-interaction domain/SIM and is sumoylated paralog-specifically; SUMO binding is experimentally documented and also inferred phylogenetically. Reason: SUMO binding is directly supported by experimental interaction with SUMO2/SUMO3 (PMID:18538659) and is consistent with the phylogenetic inference. It is a real regulatory molecular function (sumoylation impairs ubiquitin binding/hydrolysis), though it is auxiliary to the core deubiquitinase activity. Supporting Evidence: file:human/USP25/USP25-uniprot.txt Interacts with SUMO3; the interaction sumoylates efficiently USP25. |
| GO:0004843 cysteine-type deubiquitinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (InterPro/EC) annotation of cysteine-type deubiquitinase activity, the core catalytic function of USP25, fully corroborated by experimental evidence. Reason: USP25 is a peptidase C19 family cysteine protease (EC 3.4.19.12) with active-site Cys-178; this IEA agrees with EXP/IDA catalytic-activity evidence and is the core molecular function. Supporting Evidence: file:human/USP25/USP25-uniprot.txt EC=3.4.19.12 |
| GO:0005634 nucleus | IEA GO_REF:0000044 | MARK AS OVER ANNOTATED | Summary: Electronic localization to the nucleus from a UniProt subcellular-location keyword. USP25 is principally cytoplasmic; nuclear localization is only weakly supported (transient punctate nuclear signal of the USP25m isoform in myotubes). Reason: The strong experimental evidence places USP25 in the cytoplasm/cytosol; nuclear localization rests on an IEA keyword and an inferred-by-similarity note limited to transient USP25m signal in differentiating myotubes, so it is not a robust general localization. Supporting Evidence: file:human/USP25/USP25-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic cytoplasmic localization, consistent with strong experimental evidence for cytoplasmic USP25. Reason: Multiple EXP/IDA studies localize USP25 to the cytoplasm; this IEA agrees with the experimentally supported compartment. Supporting Evidence: file:human/USP25/USP25-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0016579 protein deubiquitination | IEA GO_REF:0000002 | ACCEPT | Summary: Electronic annotation of protein deubiquitination, the biological process executed by USP25's catalytic activity; well supported. Reason: Protein deubiquitination is the direct process outcome of USP25's cysteine-type deubiquitinase activity and is corroborated by multiple experimental studies. Supporting Evidence: file:human/USP25/USP25-uniprot.txt Deubiquitinating enzyme that hydrolyzes ubiquitin moieties conjugated to substrates |
| GO:0005515 protein binding | IPI PMID:21516116 Next-generation sequencing to generate interactome datasets. | KEEP AS NON CORE | Summary: IntAct interaction with SYK (P43405), a validated USP25 partner (SYK phosphorylates USP25 and regulates its levels). The bare protein binding term is uninformative. Reason: Records a real interaction (SYK), but per curation guidelines bare protein binding is uninformative and not a core function; the SYK relationship is captured in regulation rather than as a molecular function. Supporting Evidence: file:human/USP25/USP25-uniprot.txt Q9UHP3; P43405: SYK |
| GO:0005515 protein binding | IPI PMID:22153077 Structural basis and sequence rules for substrate recognitio... | KEEP AS NON CORE | Summary: IntAct interaction with TNKS2 (Q9H2K2), a validated USP25 substrate (USP25 deubiquitinates and stabilizes tankyrases). The bare protein binding term is uninformative; the biologically meaningful relationship is enzyme-substrate. Reason: Real and functionally relevant interaction (TNKS2), but bare protein binding is uninformative as a molecular function; the substrate relationship informs the Wnt-regulation role rather than constituting a core MF. Supporting Evidence: file:human/USP25/USP25-uniprot.txt Q9UHP3; Q9H2K2: TNKS2 |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: High-throughput yeast two-hybrid interactome capturing USP25 interactions with MAGEB4, SYK, RAD23A, SUMO2 and ZNF426. The bare protein binding term is uninformative. Reason: Records real high-throughput interactions but bare protein binding is uninformative and not core; SUMO2 binding and SYK are captured elsewhere. Supporting Evidence: file:human/USP25/USP25-uniprot.txt Q9UHP3; O15481: MAGEB4 |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | KEEP AS NON CORE | Summary: IntAct interactions with the proteasome-shuttle UBA-domain proteins RAD23A/RAD23B (P54725/P54727). The bare protein binding term is uninformative. Reason: Records recurrent interactions with RAD23A/B but bare protein binding is uninformative and not a core molecular function. Supporting Evidence: file:human/USP25/USP25-uniprot.txt Q9UHP3; P54725: RAD23A |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | KEEP AS NON CORE | Summary: IntAct interaction with RAD23A (P54725). The bare protein binding term is uninformative. Reason: Records a real interaction but bare protein binding is uninformative and not core. Supporting Evidence: file:human/USP25/USP25-uniprot.txt Q9UHP3; P54725: RAD23A |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Multi-partner IntAct screen (RAD23A/B, PUS10, TMEM43, MID2 and others). The bare protein binding term is uninformative. Reason: Records real high-throughput interactions but bare protein binding is uninformative and not core. Supporting Evidence: file:human/USP25/USP25-uniprot.txt Q9UHP3; Q3MIT2: PUS10 |
| GO:0005515 protein binding | IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro... | KEEP AS NON CORE | Summary: IntAct interaction with SYK (P43405), a validated partner. The bare protein binding term is uninformative. Reason: Records a real interaction (SYK) but bare protein binding is uninformative and not core. Supporting Evidence: file:human/USP25/USP25-uniprot.txt Q9UHP3; P43405: SYK |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: Neurodegeneration interactome screen capturing interactions with PRKACA, TGFBR2 and RAD23A. The bare protein binding term is uninformative. Reason: Records high-throughput interactions but bare protein binding is uninformative and not core. Supporting Evidence: file:human/USP25/USP25-uniprot.txt Q9UHP3; P17612: PRKACA |
| GO:0005515 protein binding | IPI PMID:33060197 Comparative host-coronavirus protein interaction networks re... | KEEP AS NON CORE | Summary: IntAct interaction with the SARS-CoV-2 replicase polyprotein (P0DTD1) from a viral-host interactome screen. The bare protein binding term is uninformative. Reason: Records a viral-interactome interaction but bare protein binding is uninformative and not a core function of USP25. Supporting Evidence: file:human/USP25/USP25-uniprot.txt PRO_0000449633 [P0DTD1]: rep |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: BioPlex affinity-purification interactome capturing interactions with GDI1 and RAD23B. The bare protein binding term is uninformative. Reason: Records high-throughput interactions but bare protein binding is uninformative and not core. Supporting Evidence: file:human/USP25/USP25-uniprot.txt Q9UHP3; P31150: GDI1 |
| GO:0005515 protein binding | IPI PMID:34232536 Interactomes of SARS-CoV-2 and human coronaviruses reveal ho... | KEEP AS NON CORE | Summary: IntAct interaction with the SARS-CoV-2 replicase polyprotein (P0DTD1) from a viral-host interactome study. The bare protein binding term is uninformative. Reason: Records a viral-interactome interaction but bare protein binding is uninformative and not core. Supporting Evidence: file:human/USP25/USP25-uniprot.txt PRO_0000449633 [P0DTD1]: rep |
| GO:0005515 protein binding | IPI PMID:35914814 Chr21 protein-protein interactions: enrichment in proteins i... | KEEP AS NON CORE | Summary: IntAct screen capturing interactions with GDI1, RAD23B and TNKS2. The bare protein binding term is uninformative; the TNKS2 interaction is a validated substrate relationship. Reason: Records real interactions including the TNKS2 substrate, but bare protein binding is uninformative and not a core molecular function. Supporting Evidence: file:human/USP25/USP25-uniprot.txt Q9UHP3; Q9H2K2: TNKS2 |
| GO:0005515 protein binding | IPI PMID:36217029 A proteome-scale map of the SARS-CoV-2-human contactome. | KEEP AS NON CORE | Summary: IntAct interaction with the SARS-CoV-2 replicase polyprotein (P0DTD1). The bare protein binding term is uninformative. Reason: Records a viral-interactome interaction but bare protein binding is uninformative and not core. Supporting Evidence: file:human/USP25/USP25-uniprot.txt PRO_0000449633 [P0DTD1]: rep |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | KEEP AS NON CORE | Summary: Multimodal cell-maps interactome capturing interactions with RAD23A/RAD23B. The bare protein binding term is uninformative. Reason: Records high-throughput interactions but bare protein binding is uninformative and not core. Supporting Evidence: file:human/USP25/USP25-uniprot.txt Q9UHP3; P54727: RAD23B |
| GO:0006955 immune response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic (Ensembl ortholog) annotation of immune response. USP25 has documented roles in innate immunity and inflammation (IL-17 signaling, antiviral TRAF3/ERLIN1-2), so the broad process is plausible but non-specific. Reason: USP25 participates in immune signaling but the bare "immune response" term is broad and inherited by ortholog transfer; more specific BP terms (e.g. negative regulation of IL-17 signaling) better capture the role. Supporting Evidence: file:human/USP25/USP25-uniprot.txt functions in various biological processes including inflammation and immune response |
| GO:0006979 response to oxidative stress | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic (ortholog) annotation of response to oxidative stress. USP25 regulates the KEAP1-NRF2 anti-oxidation axis, making the process plausible, though its specific role is negative regulation (stabilizing KEAP1, promoting NRF2 degradation). Reason: Supported in spirit by the KEAP1-NRF2 role, but the IDA term "negative regulation of response to oxidative stress" is the more precise annotation; this broad ortholog-transferred term is non-core. Supporting Evidence: file:human/USP25/USP25-uniprot.txt Regulates KEAP1- NRF2 axis in the defense against oxidative assaults by deubiquitinating |
| GO:0016071 mRNA metabolic process | IEA GO_REF:0000107 | REMOVE | Summary: Electronic (ortholog) annotation of mRNA metabolic process. There is no direct experimental evidence in the human record linking USP25 to mRNA metabolism. Reason: No experimental or curated support ties USP25 to mRNA metabolism in the UniProt record or literature reviewed; this appears to be an over-broad ortholog-transferred annotation. Supporting Evidence: file:human/USP25/USP25-uniprot.txt Deubiquitinating enzyme that hydrolyzes ubiquitin moieties conjugated to substrates |
| GO:0031098 stress-activated protein kinase signaling cascade | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic (ortholog) annotation of SAPK signaling. USP25 influences JNK/p38 phosphorylation via TRAF3 stabilization, so a connection exists but is indirect. Reason: USP25 modulates JNK/p38 (SAPK) levels through TRAF3 stabilization, so the term is plausible but indirect and ortholog-transferred; non-core. Supporting Evidence: file:human/USP25/USP25-uniprot.txt Prevents the ubiquitination and degradation of TRAF3 to reduce the phosphorylation levels of JNK and P38 |
| GO:0065003 protein-containing complex assembly | IEA GO_REF:0000107 | REMOVE | Summary: Electronic (ortholog) annotation of protein-containing complex assembly. There is no direct evidence that USP25 functions in complex assembly as a biological role. Reason: No experimental support links USP25 to a complex-assembly process; this is an over-broad ortholog-transferred annotation. Supporting Evidence: file:human/USP25/USP25-uniprot.txt Deubiquitinating enzyme that hydrolyzes ubiquitin moieties conjugated to substrates |
| GO:0097400 interleukin-17-mediated signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic (ortholog) annotation placing USP25 in the IL-17 signaling pathway, strongly corroborated experimentally (USP25 removes K63-Ub from TRAF5/TRAF6). The validated role is negative regulation of this pathway. Reason: USP25's involvement in IL-17 signaling is well established experimentally; the more precise IDA term "negative regulation of interleukin-17-mediated signaling pathway" captures the directionality, so this broad term is retained as non-core. Supporting Evidence: PMID:23042150 USP25 interacted with TRAF5 and TRAF6, but not with TRAF3 in HBECs or MEFs after IL-17 stimulation |
| GO:0016579 protein deubiquitination | TAS Reactome:R-HSA-5688426 | ACCEPT | Summary: Reactome curated annotation of protein deubiquitination, the core process of USP25. Reason: Protein deubiquitination is the direct biological process of USP25's catalytic activity and is well supported across experimental and curated sources. Supporting Evidence: file:human/USP25/USP25-uniprot.txt Deubiquitinating enzyme that hydrolyzes ubiquitin moieties conjugated to substrates |
| GO:0004843 cysteine-type deubiquitinase activity | TAS Reactome:R-HSA-5696564 | ACCEPT | Summary: Reactome curated annotation of cysteine-type deubiquitinase activity, the core catalytic molecular function of USP25. Reason: This is the central, experimentally validated molecular function of USP25 (active-site Cys-178; EC 3.4.19.12). Supporting Evidence: file:human/USP25/USP25-uniprot.txt EC=3.4.19.12 |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence (HPA) cytosolic localization, consistent with the experimentally established cytoplasmic localization of USP25. Reason: IDA-supported cytosolic localization agrees with multiple experimental cytoplasm annotations and the gene's documented site of action. Supporting Evidence: file:human/USP25/USP25-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0004843 cysteine-type deubiquitinase activity | EXP PMID:23042150 Negative regulation of IL-17-mediated signaling and inflamma... | ACCEPT | Summary: Experimental demonstration of deubiquitinase catalytic activity in the context of removing K63-linked ubiquitin from TRAF5/TRAF6 during IL-17 signaling. Reason: Direct experimental evidence for cysteine-type deubiquitinase activity; this is the core molecular function of USP25. Supporting Evidence: PMID:23042150 USP25 interacted with TRAF5 and TRAF6, but not with TRAF3 in HBECs or MEFs after IL-17 stimulation |
| GO:0004843 cysteine-type deubiquitinase activity | EXP PMID:37339955 USP25 regulates KEAP1-NRF2 anti-oxidation axis and its inact... | ACCEPT | Summary: Experimental demonstration of deubiquitinase activity through deubiquitination and stabilization of KEAP1 (catalytic-dead C178S abolishes activity). Reason: Direct experimental support for the core cysteine-type deubiquitinase activity; C178S mutagenesis confirms catalytic dependence. Supporting Evidence: PMID:37339955 Here we report that USP25 deubiquitinates KEAP1 and prevents it from excessive ubiquitination and degradation. |
| GO:0005737 cytoplasm | EXP PMID:28619731 USP25 regulates Wnt signaling by controlling the stability o... | ACCEPT | Summary: Experimental cytoplasmic localization (from the tankyrase/Wnt study), consistent with USP25's established compartment. Reason: Experimental evidence supports cytoplasmic localization, the principal site of USP25 action. Supporting Evidence: file:human/USP25/USP25-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005737 cytoplasm | IMP PMID:38875478 Heterozygous variants in USP25 cause genetic generalized epi... | ACCEPT | Summary: Cytoplasmic localization reported alongside characterization of epilepsy-associated USP25 variants; consistent with the established cytoplasmic compartment. Reason: Supports cytoplasmic localization, agreeing with other experimental evidence. Supporting Evidence: file:human/USP25/USP25-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0101005 deubiquitinase activity | IMP PMID:38875478 Heterozygous variants in USP25 cause genetic generalized epi... | MODIFY | Summary: Deubiquitinase activity assayed for epilepsy-associated USP25 variants; a C-terminal truncation is a gain-of-function increasing deubiquitination. This is the parent term of the more precise cysteine-type deubiquitinase activity. Reason: GO:0101005 (deubiquitinase activity) is correct but less precise than the mechanistically defined GO:0004843 (cysteine-type deubiquitinase activity) already annotated for USP25; using the specific term is preferable. Proposed replacements: cysteine-type deubiquitinase activity Supporting Evidence: file:human/USP25/USP25-uniprot.txt gain-of-function variant resulting in increased protein deubiquitination |
| GO:0005737 cytoplasm | IDA PMID:19440361 The UBA-UIM domains of the USP25 regulate the enzyme ubiquit... | ACCEPT | Summary: Direct evidence that USP25 is active in the cytoplasm, where its UBA-UIM domains regulate ubiquitination state and substrate recognition. Reason: The is_active_in cytoplasm annotation correctly places USP25's deubiquitinase activity in its principal compartment, with direct experimental support. Supporting Evidence: file:human/USP25/USP25-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0101005 deubiquitinase activity | IDA PMID:37339955 USP25 regulates KEAP1-NRF2 anti-oxidation axis and its inact... | MODIFY | Summary: Direct assay of deubiquitinase activity (KEAP1 deubiquitination). This is the parent of the more precise cysteine-type deubiquitinase activity term. Reason: GO:0101005 is correct but less precise; USP25 is a cysteine-type DUB (Cys-178), so GO:0004843 is the appropriate specific molecular function. Proposed replacements: cysteine-type deubiquitinase activity Supporting Evidence: PMID:37339955 Here we report that USP25 deubiquitinates KEAP1 and prevents it from excessive ubiquitination and degradation. |
| GO:1902883 negative regulation of response to oxidative stress | IDA PMID:37339955 USP25 regulates KEAP1-NRF2 anti-oxidation axis and its inact... | ACCEPT | Summary: USP25 negatively regulates the oxidative-stress response by deubiquitinating and stabilizing KEAP1, which promotes degradation of the antioxidant transcription factor NRF2; loss of USP25 is protective in acetaminophen liver injury. Reason: Directly supported experimentally; captures USP25's specific role in the KEAP1-NRF2 axis with correct directionality. Supporting Evidence: PMID:37339955 Here we report that USP25 deubiquitinates KEAP1 and prevents it from excessive ubiquitination and degradation. |
| GO:0005737 cytoplasm | IDA PMID:2304215 Problems identified by secondary review of accepted manuscri... | KEEP AS NON CORE | Summary: is_active_in cytoplasm annotation. The cited reference PMID:2304215 (a 1990 paper) predates USP25 characterization and appears to be an incorrect/legacy citation, but the cytoplasmic site of activity itself is well supported by other experimental evidence. Reason: The cytoplasmic activity location is correct and redundantly supported by stronger evidence (PMID:19440361); however the specific reference appears to be a citation error, so the annotation is retained but not relied upon. Supporting Evidence: file:human/USP25/USP25-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0101005 deubiquitinase activity | IDA PMID:23042150 Negative regulation of IL-17-mediated signaling and inflamma... | MODIFY | Summary: Direct assay of deubiquitinase activity (removal of K63-linked ubiquitin from TRAF5/TRAF6). This is the parent of the more precise cysteine-type deubiquitinase activity term. Reason: GO:0101005 is correct but less precise; USP25 is a cysteine-type DUB, so GO:0004843 is the appropriate specific molecular function. Proposed replacements: cysteine-type deubiquitinase activity Supporting Evidence: PMID:23042150 USP25 interacted with TRAF5 and TRAF6, but not with TRAF3 in HBECs or MEFs after IL-17 stimulation |
| GO:1903882 negative regulation of interleukin-17-mediated signaling pathway | IDA PMID:23042150 Negative regulation of IL-17-mediated signaling and inflamma... | ACCEPT | Summary: USP25 negatively regulates IL-17 signaling and inflammation by removing K63-linked ubiquitin chains from the adaptors TRAF5 and TRAF6, dampening downstream activation. Reason: Directly and specifically supported experimentally; captures USP25's role in restraining IL-17 signaling with correct directionality. Supporting Evidence: PMID:23042150 USP25 interacted with TRAF5 and TRAF6, but not with TRAF3 in HBECs or MEFs after IL-17 stimulation |
| GO:0032183 SUMO binding | IPI PMID:18538659 Mechanism and consequences for paralog-specific sumoylation ... | ACCEPT | Summary: Experimental interaction with SUMO (SUMO2/3 preferred) via the N-terminal SIM, mediating paralog-specific sumoylation that impairs USP25 ubiquitin binding and hydrolysis. Reason: Directly documented SUMO binding through the SUMO-interaction motif; a genuine regulatory molecular function (auxiliary to the core DUB activity). Supporting Evidence: file:human/USP25/USP25-uniprot.txt Interacts with SUMO3; the interaction sumoylates efficiently USP25. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5696564 | ACCEPT | Summary: Reactome curated cytosolic localization, consistent with the experimentally established cytoplasmic/cytosolic localization of USP25. Reason: Agrees with IDA cytosol and multiple cytoplasm annotations. Supporting Evidence: file:human/USP25/USP25-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0019783 ubiquitin-like protein peptidase activity | NAS PMID:22590560 Ubiquitin-specific protease 25 functions in Endoplasmic Reti... | MARK AS OVER ANNOTATED | Summary: Non-author statement attributing ubiquitin-like protein peptidase activity. USP25's documented catalytic activity is deubiquitination (cysteine-type deubiquitinase); broader Ubl peptidase activity is not strongly substantiated. Reason: USP25's experimentally established activity is on ubiquitin (EC 3.4.19.12); the broader "ubiquitin-like protein peptidase activity" rests on a NAS statement and is better represented by the specific cysteine-type deubiquitinase activity. Supporting Evidence: file:human/USP25/USP25-uniprot.txt EC=3.4.19.12 |
| GO:0005783 endoplasmic reticulum | IDA PMID:22590560 Ubiquitin-specific protease 25 functions in Endoplasmic Reti... | KEEP AS NON CORE | Summary: Direct evidence for ER association in the context of USP25's ERAD function (counteracting HRD1). A genuine but context-specific localization secondary to the predominant cytoplasmic pool. Reason: ER localization is experimentally supported in the ERAD context, but it is a specialized, partial localization relative to USP25's predominant cytoplasmic site of action. Supporting Evidence: PMID:22590560 USP25 counteracts the ubiquitin ligase function of HRD1. |
| GO:0016579 protein deubiquitination | IDA PMID:22590560 Ubiquitin-specific protease 25 functions in Endoplasmic Reti... | ACCEPT | Summary: Direct evidence of protein deubiquitination, here counteracting HRD1-mediated ubiquitination of ERAD substrates and rescuing them from proteasomal degradation. Reason: Protein deubiquitination is the direct, experimentally supported process of USP25's catalytic activity. Supporting Evidence: PMID:22590560 USP25 counteracts the ubiquitin ligase function of HRD1 by binding ubiquitinated species and cleaving them. |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:22590560 Ubiquitin-specific protease 25 functions in Endoplasmic Reti... | KEEP AS NON CORE | Summary: Interaction with the E3 ubiquitin ligase HRD1/SYVN1 (Q86TM6), consistent with USP25 counteracting HRD1 to rescue ERAD substrates. Reason: A real and functionally relevant interaction (HRD1) underlying the ERAD role; informative as a binding function but auxiliary to the core deubiquitinase activity. Supporting Evidence: PMID:22590560 USP25 counteracts the ubiquitin ligase function of HRD1. |
| GO:0043130 ubiquitin binding | NAS PMID:22590560 Ubiquitin-specific protease 25 functions in Endoplasmic Reti... | ACCEPT | Summary: Ubiquitin binding via the N-terminal UBA-like and tandem UIM domains, which recognize ubiquitin/ubiquitin chains and regulate substrate engagement. Reason: Ubiquitin binding through the UBA/UIM modules is well established structurally and functionally and underlies substrate recognition by USP25. Supporting Evidence: file:human/USP25/USP25-uniprot.txt The UBA-UIM domains of the USP25 regulate the enzyme ubiquitination state and modulate substrate recognition |
| GO:0051117 ATPase binding | IPI PMID:22590560 Ubiquitin-specific protease 25 functions in Endoplasmic Reti... | KEEP AS NON CORE | Summary: Interaction with the AAA-ATPase VCP/p97 (P55072), a central ERAD component that extracts ubiquitinated substrates from the ER membrane. Reason: A real interaction relevant to USP25's ERAD role (VCP/p97), but auxiliary to the core deubiquitinase function. Supporting Evidence: PMID:22590560 USP25 counteracts the ubiquitin ligase function of HRD1. |
| GO:1904293 negative regulation of ERAD pathway | IMP PMID:22590560 Ubiquitin-specific protease 25 functions in Endoplasmic Reti... | ACCEPT | Summary: USP25 negatively regulates ERAD by counteracting HRD1-mediated ubiquitination of ERAD substrates, cleaving ubiquitin from them and rescuing them from proteasomal degradation. Reason: Directly supported experimentally; captures USP25's specific ERAD-modulating role. Supporting Evidence: PMID:22590560 USP25 counteracts the ubiquitin ligase function of HRD1 by binding ubiquitinated species and cleaving them. |
| GO:0004843 cysteine-type deubiquitinase activity | IMP PMID:18538659 Mechanism and consequences for paralog-specific sumoylation ... | ACCEPT | Summary: Deubiquitinase activity inferred from mutational analysis in the sumoylation study; sumoylation impairs ubiquitin hydrolysis. Reason: Supports the core cysteine-type deubiquitinase activity of USP25. Supporting Evidence: file:human/USP25/USP25-uniprot.txt Sumoylation impairs binding to and hydrolysis of ubiquitin chains. |
| GO:0005515 protein binding | IPI PMID:18538659 Mechanism and consequences for paralog-specific sumoylation ... | MODIFY | Summary: IntAct interaction with SUMO3 (P55854), the basis of the SUMO-binding molecular function. The bare protein binding term is uninformative; SUMO binding (GO:0032183) is the specific term. Reason: Bare protein binding is uninformative; the WITH partner is SUMO3, so SUMO binding (GO:0032183) is the appropriate specific molecular function. Proposed replacements: SUMO binding Supporting Evidence: file:human/USP25/USP25-uniprot.txt Interacts with SUMO3; the interaction sumoylates efficiently USP25. |
| GO:0070536 protein K63-linked deubiquitination | IMP PMID:18538659 Mechanism and consequences for paralog-specific sumoylation ... | ACCEPT | Summary: USP25 cleaves K63-linked polyubiquitin chains, consistent with its activity on TRAF5/TRAF6 K63 chains in IL-17 signaling. Reason: USP25's ability to hydrolyze K63-linked chains is experimentally supported and biologically relevant (IL-17/TRAF signaling). Supporting Evidence: PMID:23042150 USP25 interacted with TRAF5 and TRAF6, but not with TRAF3 in HBECs or MEFs after IL-17 stimulation |
| GO:0071108 protein K48-linked deubiquitination | IMP PMID:18538659 Mechanism and consequences for paralog-specific sumoylation ... | ACCEPT | Summary: USP25 cleaves K48-linked polyubiquitin chains, consistent with its rescue of substrates (e.g. ERAD substrates, TNKS, KEAP1) from K48-linked proteasomal degradation. Reason: USP25's activity on K48-linked chains is experimentally supported and underlies its substrate-stabilizing roles. Supporting Evidence: file:human/USP25/USP25-uniprot.txt Sumoylation impairs binding to and hydrolysis of ubiquitin chains. |
| GO:0004843 cysteine-type deubiquitinase activity | TAS PMID:10644437 USP25, a novel gene encoding a deubiquitinating enzyme, is l... | ACCEPT | Summary: Original cloning paper describing USP25 as a deubiquitinating enzyme; traceable author statement of cysteine-type deubiquitinase activity. Reason: Supports the core molecular function; consistent with all later experimental evidence. Supporting Evidence: file:human/USP25/USP25-uniprot.txt Deubiquitinating enzyme that hydrolyzes ubiquitin moieties conjugated to substrates |
| GO:0006508 proteolysis | TAS PMID:10644437 USP25, a novel gene encoding a deubiquitinating enzyme, is l... | MARK AS OVER ANNOTATED | Summary: Broad proteolysis annotation from the original cloning paper. USP25 cleaves isopeptide/peptide bonds of ubiquitin conjugates; protein deubiquitination is the precise process. Reason: Generic "proteolysis" is imprecise for a deubiquitinase; the specific process is protein deubiquitination (already annotated). Retaining the broad term adds little. Supporting Evidence: file:human/USP25/USP25-uniprot.txt Deubiquitinating enzyme that hydrolyzes ubiquitin moieties conjugated to substrates |
| GO:0008233 peptidase activity | TAS PMID:10644437 USP25, a novel gene encoding a deubiquitinating enzyme, is l... | MARK AS OVER ANNOTATED | Summary: Broad peptidase activity annotation from the original cloning paper. The precise activity is cysteine-type deubiquitinase activity (peptidase C19 family). Reason: Generic "peptidase activity" is a high-level parent; the specific GO:0004843 cysteine-type deubiquitinase activity is already annotated and is far more informative. Supporting Evidence: file:human/USP25/USP25-uniprot.txt EC=3.4.19.12 |
| GO:0036211 protein modification process | TAS PMID:10644437 USP25, a novel gene encoding a deubiquitinating enzyme, is l... | MARK AS OVER ANNOTATED | Summary: Very broad "protein modification process" annotation from the original cloning paper. The specific process (protein deubiquitination) is already annotated. Reason: This is an over-general parent term; protein deubiquitination is the precise and already-annotated process. Supporting Evidence: file:human/USP25/USP25-uniprot.txt Deubiquitinating enzyme that hydrolyzes ubiquitin moieties conjugated to substrates |
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Download this section (compressed HTML)Q: Is USP25's deubiquitinase activity directed to substrates by a shared recognition feature, or is substrate selection determined principally by context-specific scaffolds/adaptors in each pathway (Wnt, KEAP1-NRF2, IL-17, ERAD)?
Q: How does the homotetramer-to-homodimer transition (and its disruption by epilepsy-associated C-terminal truncations) couple oligomeric state to substrate-specific deubiquitination in neurons?
Q: Does the muscle-specific isoform USP25m have a distinct substrate repertoire (e.g. sarcomeric proteins MYBPC1/FLNC) compared with the ubiquitously expressed USP25a/b isoforms?
Experiment: Proteome-wide ubiquitinome (diGly) profiling comparing wild-type, catalytic-dead (C178S) and epilepsy-variant USP25 to define the global substrate landscape and test substrate-specificity hypotheses.
Experiment: Reconstitute the oligomerization switch in vitro with defined homodimer versus homotetramer assemblies and measure deubiquitination kinetics on K48- versus K63-linked chains and on physiological substrates (KEAP1, TNKS2, TRAF6).
Experiment: Neuronal models (iPSC-derived neurons) carrying EIG19 gain-of-function variants to test whether increased deubiquitination raises neuronal excitability and to identify the responsible neuronal substrates.
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