Ataxin-3 (ATXN3; also called Machado-Joseph disease protein MJD1) is a deubiquitinating enzyme of the Josephin/Machado-Joseph-domain family of papain-like cysteine proteases. Its N-terminal Josephin domain carries the catalytic triad (Cys14, His119, Asn134) that hydrolyzes isopeptide bonds in polyubiquitin, while two-to-three C-terminal ubiquitin-interacting motifs (UIMs) bind ubiquitin and set the length of the chains it engages. Ataxin-3 preferentially binds and trims long polyubiquitin chains (with weak activity on chains of four or fewer ubiquitins) and cleaves both K48- and K63-linked linkages, acting as a ubiquitin-chain-editing/trimming DUB whose activity is stimulated by the AAA-ATPase VCP/p97. Through these activities it supports protein homeostasis: it participates in endoplasmic-reticulum-associated degradation (ERAD) and retrotranslocation as a p97-associated DUB, cooperates with the proteasome-shuttle factors RAD23A/RAD23B and the ubiquitin ligase STUB1/CHIP to limit ubiquitin-chain length during protein quality control, and deubiquitinates BECN1 to promote starvation-induced autophagy. Lysosome- associated ataxin-3 deubiquitinates the GTPase RHEB to negatively regulate mTORC1 signaling during amino-acid starvation, and nuclear ataxin-3 acts as a histone-binding transcriptional regulator, partnering with FOXO4 at the SOD2/MnSOD oxidative-stress gene. The protein shuttles between cytoplasm and nucleus and associates with the nuclear matrix. A polymorphic polyglutamine (CAG) tract near the C-terminus, when expanded beyond the normal range, drives misfolding, aggregation and neuronal intranuclear inclusions, causing spinocerebellar ataxia type 3 (Machado-Joseph disease), the most common autosomal-dominant ataxia.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004843 cysteine-type deubiquitinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) inference that ataxin-3 is a cysteine-type deubiquitinase. Reason: This is the well-established core molecular function of ataxin-3, a Josephin-domain (papain-like cysteine protease) DUB. The phylogenetic inference is correctly leveled and directly corroborated by biochemical assays across Josephin-domain proteins. Supporting Evidence: PMID:17696782 possess de-ubiquitination activity |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference that ataxin-3 is active in the nucleus. Reason: Ataxin-3 shuttles between cytoplasm and nucleus and carries a nuclear localization signal; nuclear localization is experimentally established and consistent with its transcriptional and DNA-damage-associated roles. Supporting Evidence: PMID:9580663 translocates to the nucleus |
| GO:0006515 protein quality control for misfolded or incompletely synthesized proteins | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference that ataxin-3 participates in protein quality control. Reason: Ataxin-3's DUB activity underpins a central role in cellular protein quality control (ERAD, proteasomal targeting, misfolded-protein handling), well supported in the literature. Supporting Evidence: PMID:22970133 a central role for ataxin-3 in the protein quality control of the cell |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference that ataxin-3 functions in proteasomal ubiquitin-dependent degradation. Reason: Ataxin-3 edits ubiquitin chains on substrates destined for the proteasome and interacts with proteasome shuttle factors (RAD23A/B, p97); the inference is consistent with its established DUB role in the ubiquitin-proteasome system. Supporting Evidence: PMID:22970133 Ataxin-3 has been implicated in ubiquitin-proteasome pathways |
| GO:1904262 negative regulation of TORC1 signaling | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference that ataxin-3 negatively regulates TORC1 signaling. Reason: Lysosomal ataxin-3 deubiquitinates RHEB, lowering mTORC1 activity under amino-acid starvation; this direct experimental role in humans corroborates the IBA inference. Supporting Evidence: PMID:33157014 the deubiquitinase activity of ATXN3 is required for its inhibitory effect on mTORC1 activity |
| GO:1904294 positive regulation of ERAD pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference that ataxin-3 positively regulates the ERAD pathway. Reason: Ataxin-3 is a p97-associated DUB that promotes efficient degradation of misfolded ER proteins; the IBA inference matches the experimental IMP annotation from PMID:17000876. Supporting Evidence: PMID:17000876 atx3 acts in conjunction with p97 to regulate the degradation of misfolded ER proteins |
| GO:0004843 cysteine-type deubiquitinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (multi-method IEA) assignment of cysteine-type deubiquitinase activity. Reason: Electronic annotation corroborating the core, experimentally established DUB molecular function of ataxin-3. Supporting Evidence: PMID:17696782 possess de-ubiquitination activity |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic (UniProt subcellular-location mapping) assignment of nuclear localization. Reason: Nuclear localization is experimentally established; the electronic mapping is consistent with direct evidence. Supporting Evidence: PMID:9580663 translocates to the nucleus |
| GO:0005765 lysosomal membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic assignment of lysosomal membrane localization. Reason: Directly corroborated by experimental evidence that ataxin-3 acts on the lysosomal membrane to deubiquitinate RHEB under amino-acid starvation. Supporting Evidence: PMID:33157014 ATXN3 likely deubiquitinates Ub-Rheb on the lysosomal membrane |
| GO:0016363 nuclear matrix | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic assignment of nuclear matrix localization. Reason: Ataxin-3 associates with the inner nuclear matrix by direct experimental evidence, corroborating this electronic mapping. Supporting Evidence: PMID:9580663 with the inner nuclear matrix |
| GO:0016579 protein deubiquitination | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assignment of the protein deubiquitination process. Reason: The generic deubiquitination process directly reflects ataxin-3's established DUB catalytic activity. Supporting Evidence: PMID:17696782 possess de-ubiquitination activity |
| GO:0045202 synapse | IEA GO_REF:0000108 | MARK AS OVER ANNOTATED | Summary: Inter-ontology (GO_REF:0000108) inferred synapse localization, derived from the GO:0007268 chemical synaptic transmission annotation. Reason: This is not independent evidence - it is the mechanical inter-ontology consequence of the GO:0007268 (chemical synaptic transmission) TAS annotation, which this review recommends removing because its cited reference (PMID:7655453) is a clinical-genetics study with no synaptic content. Removing that root BP annotation dissolves this derived CC annotation automatically; no separate curation action is needed. Ataxin-3 is a predominantly cytoplasmic/nuclear DUB with no demonstrated synaptic-compartment role. |
| GO:0005515 protein binding | IPI PMID:16525503 An arginine/lysine-rich motif is crucial for VCP/p97-mediate... | MODIFY | Summary: Physical interaction of ataxin-3 with VCP/p97 via an arginine/lysine-rich motif. Reason: A genuine experimental interaction (ataxin-3-VCP/p97), but "protein binding" is uninformative as a molecular function. VCP/p97 is a AAA-ATPase, so the specific, informative term ATPase binding (GO:0051117) is available and should replace the generic term rather than the interaction being retained as an uninformative non-core row. Proposed replacements: ATPase binding Supporting Evidence: PMID:16525503 serves as a recognition site for the interaction with the molecular |
| GO:0005515 protein binding | IPI PMID:16713569 A protein-protein interaction network for human inherited at... | KEEP AS NON CORE | Summary: Ataxin-3 interactions identified in a large yeast two-hybrid ataxia protein interaction network. Reason: High-throughput interaction data placing ataxin-3 in the inherited-ataxia interactome. Real but generic; "protein binding" is uninformative and no single specific partner/function is conveyed. Retain as non-core interaction evidence. Supporting Evidence: PMID:16713569 protein-protein interactions using a stringent yeast two-hybrid screen |
| GO:0005515 protein binding | IPI PMID:31379806 Ataxin-3 Links NOD2 and TLR2 Mediated Innate Immune Sensing ... | KEEP AS NON CORE | Summary: Ataxin-3 interaction with the mitochondrial cristae protein MIC60 in myeloid cells (NOD2/TLR2 innate-immune signaling). Reason: A genuine experimental interaction (ataxin-3-MIC60) in the innate-immune context, but "protein binding" is uninformative as a molecular function. Retain as non-core interaction evidence noting the specific partner. Supporting Evidence: PMID:31379806 ataxin-3 associates with the mitochondrial cristae protein MIC60 |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: Ataxin-3 interactions mapped in a neurodegenerative-disease interactome. Reason: High-throughput interactome data. Real but generic; "protein binding" is uninformative and does not identify a specific functional partner. Retain as non-core interaction evidence. Supporting Evidence: PMID:32814053 generated by systematic yeast two-hybrid interaction screening of ∼500 ND-related proteins and integration of literature interactions |
| GO:0006515 protein quality control for misfolded or incompletely synthesized proteins | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic (Ensembl Compara ortholog transfer) assignment of protein quality control. Reason: Consistent with ataxin-3's established central role in cellular protein quality control via its DUB activity. Supporting Evidence: PMID:22970133 a central role for ataxin-3 in the protein quality control of the cell |
| GO:0031625 ubiquitin protein ligase binding | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic assignment of ubiquitin protein ligase binding. Reason: Ataxin-3 binds E3 ubiquitin ligases including parkin (PRKN) and CHIP/STUB1; this specific, informative binding term is supported by experimental interaction data. Supporting Evidence: PMID:24063750 we have identified the mechanism of interaction between the ubiquitin-like (Ubl) domain from parkin and three C-terminal ubiquitin-interacting motifs (UIMs) in ataxin-3 |
| GO:0035520 monoubiquitinated protein deubiquitination | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic (Ensembl Compara ortholog transfer) assignment of deubiquitination of monoubiquitinated protein. Reason: Ataxin-3's measured substrate preference argues against this specific term rather than for it. Ataxin-3 binds and cleaves LONG polyubiquitin chains and has weak activity on chains of four or fewer ubiquitins, so a mono-ubiquitin substrate is the least favourable case for this enzyme, not a representative one. No experimental demonstration of ataxin-3 acting on a monoubiquitinated substrate was found. The generic protein deubiquitination terms already capture the catalytic role; this ortholog-transferred term is over-specific in a direction the enzymology does not support. Supporting Evidence: PMID:22970133 Ataxin-3 possesses higher affinity for longer ubiquitin chains, containing at least four molecules of ubiquitin |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic assignment of proteasomal ubiquitin-dependent protein catabolism. Reason: Consistent with ataxin-3's established role in ubiquitin-proteasome-mediated degradation as a chain-editing DUB. Supporting Evidence: PMID:22970133 Ataxin-3 has been implicated in ubiquitin-proteasome pathways |
| GO:0071218 cellular response to misfolded protein | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic assignment of cellular response to misfolded protein. Reason: Ataxin-3 acts in the ERAD/misfolded-protein degradation pathway; loss of its activity triggers ER stress. Electronic annotation corroborating an established role. Supporting Evidence: PMID:17000876 atx3 acts in conjunction with p97 to regulate the degradation of misfolded ER proteins |
| GO:0016579 protein deubiquitination | TAS Reactome:R-HSA-5688426 | ACCEPT | Summary: Reactome (TAS) assertion that ataxin-3 participates in protein deubiquitination. Reason: The deubiquitination process directly reflects ataxin-3's core DUB catalytic function; well supported. Supporting Evidence: PMID:17696782 possess de-ubiquitination activity |
| GO:0004843 cysteine-type deubiquitinase activity | TAS Reactome:R-HSA-5688797 | ACCEPT | Summary: Reactome (TAS) assertion of cysteine-type deubiquitinase activity (Ub-chain cleavage). Reason: Core molecular function of ataxin-3, well supported by direct biochemical assay. Supporting Evidence: PMID:17696782 possess de-ubiquitination activity |
| GO:0004843 cysteine-type deubiquitinase activity | TAS Reactome:R-HSA-5688837 | ACCEPT | Summary: Reactome (TAS) assertion of DUB activity in the context of deubiquitinating polyUb-parkin (PARK2). Reason: Core DUB molecular function; ataxin-3 removes ubiquitin from parkin, consistent with experimental data. Supporting Evidence: PMID:24063750 can remove ubiquitin from parkin |
| GO:0004843 cysteine-type deubiquitinase activity | EXP PMID:17696782 Josephin domain-containing proteins from a variety of specie... | ACCEPT | Summary: Direct experimental demonstration that the ataxin-3 Josephin domain is an active deubiquitinating enzyme. Reason: Primary experimental evidence establishing ataxin-3's core cysteine-type deubiquitinase molecular function; the strongest support for this term. Supporting Evidence: PMID:17696782 possess de-ubiquitination activity |
| GO:0005634 nucleus | EXP PMID:30455355 Physiological and pathophysiological characteristics of atax... | ACCEPT | Summary: Experimental analysis of ataxin-3 isoforms showing (isoform-dependent) nuclear localization. Reason: Ataxin-3 isoforms differ in subcellular distribution, with nuclear localization documented; consistent with the established nuclear-cytoplasmic shuttling of ataxin-3. Supporting Evidence: PMID:30455355 ataxin-3 isoforms differ in their enzymatic deubiquitination activity, subcellular distribution, and interaction with other proteins |
| GO:0016363 nuclear matrix | EXP PMID:9580663 Ataxin-3 is transported into the nucleus and associates with... | ACCEPT | Summary: Direct experimental evidence that ataxin-3 associates with the inner nuclear matrix. Reason: Confocal microscopy and biochemical fractionation show nuclear-matrix association of endogenous, normal-repeat ataxin-3; strong primary evidence. Supporting Evidence: PMID:9580663 with the inner nuclear matrix |
| GO:1904327 protein localization to cytosolic proteasome complex | IMP PMID:17000876 Regulation of retrotranslocation by p97-associated deubiquit... | ACCEPT | Summary: Ataxin-3 promotes transfer of ubiquitinated substrates from p97 to the proteasome (delivery to the cytosolic proteasome). Reason: A catalytically inactive ataxin-3 (C14A) blocks the transfer of substrates from p97 to the proteasome, causing their accumulation on p97; supports a role in delivering substrates to the proteasome. Supporting Evidence: PMID:17000876 atx3 C14A likely blocks the transfer of substrates from p97 to the proteasome |
| GO:2000060 positive regulation of ubiquitin-dependent protein catabolic process | IDA PMID:17000876 Regulation of retrotranslocation by p97-associated deubiquit... | ACCEPT | Summary: Ataxin-3 promotes p97-associated deubiquitination facilitating substrate degradation. Reason: Direct assays show ataxin-3 promotes p97-associated deubiquitination in cells and in vitro, facilitating substrate transfer to and degradation by the proteasome (positive regulation of ubiquitin-dependent catabolism). Supporting Evidence: PMID:17000876 atx3 can promote PAD both in intact cells and in vitro |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5688786 | ACCEPT | Summary: Reactome (TAS) nucleoplasm localization (ATXN3 binds RAD23 reaction context). Reason: Nuclear/nucleoplasmic localization of ataxin-3 is experimentally established. Supporting Evidence: PMID:9580663 translocates to the nucleus |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5688834 | ACCEPT | Summary: Reactome (TAS) nucleoplasm localization (ATXN3 binds VCP reaction context). Reason: Nuclear/nucleoplasmic localization of ataxin-3 is experimentally established. Supporting Evidence: PMID:9580663 translocates to the nucleus |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9617832 | ACCEPT | Summary: Reactome (TAS) nucleoplasm localization (FOXO4:ATXN3 binds SOD2 promoter reaction context). Reason: Consistent with ataxin-3's nuclear localization and its FOXO4-associated transcriptional regulation at the nucleoplasm. Supporting Evidence: PMID:9580663 translocates to the nucleus |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9617927 | ACCEPT | Summary: Reactome (TAS) nucleoplasm localization (FOXO4 binds ATXN3 reaction context). Reason: Consistent with ataxin-3's established nuclear localization. Supporting Evidence: PMID:9580663 translocates to the nucleus |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5688797 | ACCEPT | Summary: Reactome (TAS) cytosolic localization (Ub-chain cleavage reaction context). Reason: Ataxin-3 is predominantly a cytoplasmic/cytosolic protein by direct evidence. Supporting Evidence: PMID:9124802 predominantly a cytoplasmic protein |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5688837 | ACCEPT | Summary: Reactome (TAS) cytosolic localization (deubiquitinates polyUb-PARK2 reaction context). Reason: Ataxin-3 is predominantly a cytoplasmic/cytosolic protein by direct evidence. Supporting Evidence: PMID:9124802 predominantly a cytoplasmic protein |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5689085 | ACCEPT | Summary: Reactome (TAS) cytosolic localization (ATXN3 binds polyUb-PARK2 reaction context). Reason: Ataxin-3 is predominantly a cytoplasmic/cytosolic protein by direct evidence. Supporting Evidence: PMID:9124802 predominantly a cytoplasmic protein |
| GO:0004843 cysteine-type deubiquitinase activity | IDA PMID:33157014 Amino Acids Enhance Polyubiquitination of Rheb and Its Bindi... | ACCEPT | Summary: Direct assay showing purified ataxin-3 (but not the C14A active-site mutant) deubiquitinates Ub-RHEB in vitro. Reason: Primary in vitro biochemical demonstration of ataxin-3 cysteine-type DUB activity on a physiological substrate; strong support for the core molecular function. Supporting Evidence: PMID:33157014 the wild-type ATXN3 but not the ATXN3 C14A mutant purified from bacteria deubiquitinated Ub-Rheb in vitro |
| GO:0005765 lysosomal membrane | IDA PMID:33157014 Amino Acids Enhance Polyubiquitination of Rheb and Its Bindi... | ACCEPT | Summary: Ataxin-3 localizes to and is catalytically active on the lysosomal membrane, where it deubiquitinates RHEB. Reason: Direct evidence that ataxin-3 acts on the lysosomal membrane (deubiquitinating Ub-RHEB) under amino-acid starvation; the is_active_in qualifier is well justified. Supporting Evidence: PMID:33157014 ATXN3 likely deubiquitinates Ub-Rheb on the lysosomal membrane |
| GO:0034198 cellular response to amino acid starvation | IDA PMID:33157014 Amino Acids Enhance Polyubiquitination of Rheb and Its Bindi... | ACCEPT | Summary: Amino-acid starvation drives ataxin-3 to the lysosome to deubiquitinate RHEB and restrain mTORC1. Reason: Direct evidence links ataxin-3 activity to the amino-acid-starvation response; amino acids release ataxin-3 from the lysosome, coupling nutrient status to RHEB ubiquitination and mTORC1 activity. Supporting Evidence: PMID:33157014 amino acids induce the dissociation of ATXN3 from the lysosome, which relieves the lysosomal Ub-Rheb from ATXN3-dependent deubiquitination |
| GO:1904262 negative regulation of TORC1 signaling | IDA PMID:33157014 Amino Acids Enhance Polyubiquitination of Rheb and Its Bindi... | ACCEPT | Summary: Ataxin-3 deubiquitinase activity is required to inhibit mTORC1 activity. Reason: Direct experimental evidence that the DUB activity of ataxin-3 is required for its inhibitory effect on mTORC1; a well-supported physiological process role. Supporting Evidence: PMID:33157014 the deubiquitinase activity of ATXN3 is required for its inhibitory effect on mTORC1 activity |
| GO:0005515 protein binding | IPI PMID:30455355 Physiological and pathophysiological characteristics of atax... | KEEP AS NON CORE | Summary: Isoform-specific ataxin-3 protein interactions from the isoform characterization study. Reason: Genuine experimental interaction data, but "protein binding" is uninformative as a molecular function and no specific functional partner is captured by the term. Retain as non-core interaction evidence. Supporting Evidence: PMID:30455355 ataxin-3 isoforms differ in their enzymatic deubiquitination activity, subcellular distribution, and interaction with other proteins |
| GO:0005515 protein binding | IPI PMID:21625540 Co-chaperone HSJ1a dually regulates the proteasomal degradat... | MODIFY | Summary: Interaction of ataxin-3 with the co-chaperone HSJ1a (DNAJB2), regulating its proteasomal degradation. Reason: A genuine experimental interaction (ataxin-3-HSJ1a), but "protein binding" is uninformative as a molecular function. HSJ1a/DNAJB2 is a DnaJ/Hsp40 co-chaperone, so the specific, informative term protein-folding chaperone binding (GO:0051087) is available and should replace the generic term. Proposed replacements: protein-folding chaperone binding Supporting Evidence: PMID:21625540 effects of HSJ1a on the protein levels of both normal and the disease--related |
| GO:1904294 positive regulation of ERAD pathway | IMP PMID:17000876 Regulation of retrotranslocation by p97-associated deubiquit... | ACCEPT | Summary: Ataxin-3 is required for efficient ERAD; a catalytically inactive mutant inhibits degradation of misfolded ER proteins and triggers ER stress. Reason: Mutational (IMP) evidence that ataxin-3, as a p97-associated DUB, positively regulates ER-associated degradation; a well-supported, direct biological-process role. Supporting Evidence: PMID:17000876 atx3 acts in conjunction with p97 to regulate the degradation of misfolded ER proteins |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:24068323 A deubiquitinase negatively regulates retro-translocation of... | ACCEPT | Summary: Ataxin-3 interaction with a ubiquitin (E3) ligase in the ERAD/retro-translocation context. Reason: A specific, informative binding term consistent with ataxin-3's documented interactions with E3 ubiquitin ligases (e.g. CHIP/STUB1, parkin) within the ERAD machinery. Curator experimental annotation; the cached record is abstract-only (foregrounding YOD1), so the specific supporting text is in full text not in cache and I defer to the curator rather than overrule. |
| GO:0005515 protein binding | IPI PMID:17000876 Regulation of retrotranslocation by p97-associated deubiquit... | KEEP AS NON CORE | Summary: Ataxin-3 interactions with the retrotranslocation/ERAD machinery (p97, Derlin-1, VIMP, Hrd1). Reason: Genuine experimental interactions, but "protein binding" is uninformative; the more specific ATPase binding (GO:0051117, for p97) is preferable. Retain as non-core interaction evidence. Supporting Evidence: PMID:17000876 a fraction of atx3 is associated with the ER membranes via interactions with components of the retrotranslocation machinery |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:17000876 Regulation of retrotranslocation by p97-associated deubiquit... | ACCEPT | Summary: A fraction of ataxin-3 transiently associates with the ER membrane via p97 and the Derlin-VIMP complex. Reason: Direct evidence of transient ER-membrane association; the colocalizes_with qualifier appropriately reflects the transient, machinery-dependent nature of the localization. Supporting Evidence: PMID:17000876 a fraction of atx3 is associated with the ER membranes via interactions with components of the retrotranslocation machinery |
| GO:0051117 ATPase binding | IPI PMID:17000876 Regulation of retrotranslocation by p97-associated deubiquit... | ACCEPT | Summary: Ataxin-3 binds the AAA-ATPase p97/VCP via the p97 N-domain. Reason: A specific, informative molecular-function term. Direct binding assays show ataxin-3 binds p97 (an ATPase) via its N-domain; strong support. Supporting Evidence: PMID:17000876 atx3 binds p97 via its N-domain |
| GO:0005759 mitochondrial matrix | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Sequence-similarity (ISS, from mouse Q9CVD2) assignment of mitochondrial matrix localization. Reason: Ataxin-3 is predominantly a cytoplasmic/nuclear DUB. A weak ISS transfer from mouse to the mitochondrial matrix is not corroborated in human; the only mitochondrial link (MIC60/cristae in myeloid cells) is an outer-cristae association, not matrix. Over-annotation. |
| GO:0006511 ubiquitin-dependent protein catabolic process | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity assignment of ubiquitin-dependent protein catabolism. Reason: Consistent with ataxin-3's established role in the ubiquitin-proteasome system as a chain-editing DUB. Supporting Evidence: PMID:22970133 Ataxin-3 has been implicated in ubiquitin-proteasome pathways |
| GO:0031966 mitochondrial membrane | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Sequence-similarity (ISS, from mouse) assignment of mitochondrial membrane localization. Reason: Ataxin-3 is not primarily a mitochondrial protein; the ISS transfer is weak and not corroborated in human. Although ataxin-3 can associate with the cristae protein MIC60 in myeloid cells (PMID:31379806), this specialized context does not justify a general mitochondrial-membrane localization. Over-annotation. |
| GO:0034605 cellular response to heat | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity assignment of a role in the cellular response to heat. Reason: Ataxin-3 has been implicated in the cytoprotective response to heat-shock stress, but this is a peripheral, context-dependent role rather than its core DUB molecular function. Retain as non-core. Supporting Evidence: PMID:22970133 the cytoprotective response to heat shock stress |
| GO:0042405 nuclear inclusion body | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Sequence-similarity assignment of localization to nuclear inclusion bodies. Reason: Nuclear inclusion bodies form only from polyglutamine-EXPANDED ataxin-3 and are the pathological hallmark of MJD/SCA3, not a compartment the wild-type protein normally occupies. For a normal-function review this is a localization of the disease-state aggregate rather than of the gene product, so over-annotation is the better fit than retaining it as a non-core normal location. Supporting Evidence: PMID:10915768 forms intranuclear inclusions |
| GO:0005634 nucleus | IDA PMID:24548080 CDK5 protects from caspase-induced Ataxin-3 cleavage and neu... | ACCEPT | Summary: Direct evidence of ataxin-3 (intranuclear) localization in the CDK5/caspase-cleavage study. Reason: Ataxin-3 is present in the nucleus (including intranuclear inclusion bodies in disease); consistent with its established nuclear localization. Supporting Evidence: PMID:24548080 mutation of Ataxin-3 results in aggregation of misfolded protein, formation of intranuclear as well as cytosolic inclusion bodies and cell death in distinct neuronal populations |
| GO:0005829 cytosol | IDA PMID:24548080 CDK5 protects from caspase-induced Ataxin-3 cleavage and neu... | ACCEPT | Summary: Direct evidence of ataxin-3 cytosolic localization in the CDK5/caspase-cleavage study. Reason: Ataxin-3 is present in the cytosol (including cytosolic inclusion bodies in disease); consistent with its predominantly cytoplasmic distribution. Supporting Evidence: PMID:24548080 as well as cytosolic inclusion bodies and cell death in distinct neuronal |
| GO:0005515 protein binding | IPI PMID:22970133 Valosin-containing protein (VCP/p97) is an activator of wild... | KEEP AS NON CORE | Summary: Ataxin-3 interactions with hHR23A (RAD23A) and VCP/p97 confirmed biochemically. Reason: Genuine experimental interactions, but "protein binding" is uninformative; for the VCP/p97 interaction the more specific ATPase binding (GO:0051117) is preferable. Retain as non-core interaction evidence. Supporting Evidence: PMID:22970133 We confirmed ataxin-3 affinity for both hHR23A and VCP/p97 |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:24063750 Ataxin-3 is a multivalent ligand for the parkin Ubl domain. | ACCEPT | Summary: Ataxin-3 binds the parkin (PRKN) ubiquitin-like domain via its UIMs; parkin is an E3 ubiquitin ligase. Reason: A specific, informative molecular-function term. NMR-mapped multivalent interaction between ataxin-3 UIMs and the E3 ligase parkin; ataxin-3 can remove ubiquitin from parkin. Strong support. Supporting Evidence: PMID:24063750 can remove ubiquitin from parkin |
| GO:0051117 ATPase binding | IPI PMID:22970133 Valosin-containing protein (VCP/p97) is an activator of wild... | ACCEPT | Summary: Ataxin-3 binds the AAA-ATPase VCP/p97, which activates wild-type ataxin-3. Reason: A specific, informative molecular-function term. Ataxin-3 binds VCP/p97 (a 97 kDa AAA ATPase), and this ATPase activates wild-type ataxin-3 DUB activity; strong support. Supporting Evidence: PMID:22970133 VCP/p97 protein is a 97 kDa AAA ATPase |
| GO:1990380 K48-linked deubiquitinase activity | IDA PMID:22970133 Valosin-containing protein (VCP/p97) is an activator of wild... | ACCEPT | Summary: Direct assay of ataxin-3 activity on K48-linked ubiquitin chains. Reason: In vitro protease assays used K48-linked hexa-ubiquitin chains as substrate, demonstrating linkage-specific K48 DUB activity. A well-supported, appropriately specific molecular-function term. Supporting Evidence: PMID:22970133 ataxin-3 continued to cleave K63-linked chains more robustly than K48-linked ubiquitin chains |
| GO:0061578 K63-linked deubiquitinase activity | IDA PMID:22970133 Valosin-containing protein (VCP/p97) is an activator of wild... | ACCEPT | Summary: Direct assay of ataxin-3 activity on K63-linked ubiquitin chains. Reason: In vitro protease assays used K63-linked hexa-ubiquitin chains, and ataxin-3 preferentially cleaves K63 linkages. A well-supported, appropriately specific molecular-function term. Supporting Evidence: PMID:22970133 preferentially cleaves linkages between ubiquitin molecules established through lysine 63 (K63) |
| GO:0070536 protein K63-linked deubiquitination | IDA PMID:22970133 Valosin-containing protein (VCP/p97) is an activator of wild... | ACCEPT | Summary: Ataxin-3 cleaves K63-linked polyubiquitin chains (K63-linkage deubiquitination process). Reason: Process term directly reflecting ataxin-3's demonstrated preferential cleavage of K63-linked chains; well supported. Supporting Evidence: PMID:22970133 preferentially cleaves linkages between ubiquitin molecules established through lysine 63 (K63) |
| GO:0071108 protein K48-linked deubiquitination | IDA PMID:22970133 Valosin-containing protein (VCP/p97) is an activator of wild... | ACCEPT | Summary: Ataxin-3 cleaves K48-linked polyubiquitin chains (K48-linkage deubiquitination process). Reason: Process term directly reflecting ataxin-3 activity assayed on K48-linked ubiquitin chains; well supported. Supporting Evidence: PMID:22970133 incubated with 250 nM K63 or K48 linked hexa-ubiquitin chains |
| GO:0004843 cysteine-type deubiquitinase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity assignment of cysteine-type deubiquitinase activity. Reason: Corroborates the core, experimentally established DUB molecular function of ataxin-3. Supporting Evidence: PMID:17696782 possess de-ubiquitination activity |
| GO:0006515 protein quality control for misfolded or incompletely synthesized proteins | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity assignment of protein quality control. Reason: Consistent with ataxin-3's established central role in cellular protein quality control. Supporting Evidence: PMID:22970133 a central role for ataxin-3 in the protein quality control of the cell |
| GO:0031625 ubiquitin protein ligase binding | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity assignment of ubiquitin protein ligase binding. Reason: Ataxin-3 binds E3 ubiquitin ligases (parkin, CHIP/STUB1); a specific, informative binding term corroborated by experimental interaction data. Supporting Evidence: PMID:24063750 can remove ubiquitin from parkin |
| GO:0035520 monoubiquitinated protein deubiquitination | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Sequence-similarity assignment of deubiquitination of monoubiquitinated protein. Reason: Same objection as the GO_REF:0000107 row for this term. Ataxin-3 prefers long polyubiquitin chains and is weakly active on chains of four or fewer ubiquitins, so monoubiquitinated substrate is the case its enzymology least supports. The similarity-transferred term is over-specific in an unsupported direction; the generic deubiquitination terms already carry the catalytic role. Supporting Evidence: PMID:22970133 Ataxin-3 possesses higher affinity for longer ubiquitin chains, containing at least four molecules of ubiquitin |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity assignment of proteasomal ubiquitin-dependent protein catabolism. Reason: Consistent with ataxin-3's established role in the ubiquitin-proteasome system. Supporting Evidence: PMID:22970133 Ataxin-3 has been implicated in ubiquitin-proteasome pathways |
| GO:0071218 cellular response to misfolded protein | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity assignment of cellular response to misfolded protein. Reason: Consistent with ataxin-3's established role in ERAD/misfolded-protein degradation. Supporting Evidence: PMID:17000876 atx3 acts in conjunction with p97 to regulate the degradation of misfolded ER proteins |
| GO:0000226 microtubule cytoskeleton organization | IMP PMID:20637808 Absence of ataxin-3 leads to cytoskeletal disorganization an... | KEEP AS NON CORE | Summary: siRNA depletion of ataxin-3 disrupts the microtubule network. Reason: The cytoskeletal phenotype (including compromised microtubules) is a downstream/indirect consequence of ataxin-3 depletion, not its core molecular role. The paper supports an effect on cytoskeletal organization; retain as non-core. Supporting Evidence: PMID:20637808 networks are severely compromised and disorganized |
| GO:0010810 regulation of cell-substrate adhesion | IMP PMID:20637808 Absence of ataxin-3 leads to cytoskeletal disorganization an... | KEEP AS NON CORE | Summary: Ataxin-3 depletion impairs cell-extracellular matrix adhesion (reduced talin at focal adhesions, loss of adhesion protrusions). Reason: A downstream/indirect phenotype of ataxin-3 knockdown rather than a core molecular role. The paper supports an effect on cell-substrate adhesion; retain as non-core. Supporting Evidence: PMID:20637808 Cell-extracellular matrix connection is also affected in ATXN3-depleted cells |
| GO:0030036 actin cytoskeleton organization | IMP PMID:20637808 Absence of ataxin-3 leads to cytoskeletal disorganization an... | KEEP AS NON CORE | Summary: siRNA depletion of ataxin-3 disrupts the microfilament (actin) network. Reason: The actin/microfilament disorganization is a downstream/indirect consequence of ataxin-3 depletion, not its core molecular role. The paper supports the effect; retain as non-core. Supporting Evidence: PMID:20637808 networks are severely compromised and disorganized |
| GO:0045104 intermediate filament cytoskeleton organization | IMP PMID:20637808 Absence of ataxin-3 leads to cytoskeletal disorganization an... | KEEP AS NON CORE | Summary: siRNA depletion of ataxin-3 disrupts the intermediate filament network. Reason: Intermediate-filament disorganization is a downstream/indirect consequence of ataxin-3 depletion, not its core molecular role. The paper supports the effect; retain as non-core. Supporting Evidence: PMID:20637808 intermediate filament networks are severely compromised and disorganized |
| GO:0005654 nucleoplasm | TAS PMID:9580663 Ataxin-3 is transported into the nucleus and associates with... | ACCEPT | Summary: Ataxin-3 is transported into the nucleus (nucleoplasm/nuclear matrix). Reason: Direct experimental evidence that endogenous normal-repeat ataxin-3 localizes to the nucleus; well supported. Supporting Evidence: PMID:9580663 translocates to the nucleus |
| GO:0005737 cytoplasm | TAS PMID:9124802 Machado-Joseph disease gene product is a cytoplasmic protein... | ACCEPT | Summary: Ataxin-3 is predominantly a cytoplasmic protein widely expressed in brain. Reason: Direct immunolocalization evidence that ataxin-3 is predominantly cytoplasmic; strong support for this localization. Supporting Evidence: PMID:9124802 predominantly a cytoplasmic protein |
| GO:0006289 nucleotide-excision repair | TAS PMID:10915768 Ataxin-3, the MJD1 gene product, interacts with the two huma... | MARK AS OVER ANNOTATED | Summary: TAS assignment of nucleotide-excision repair based on ataxin-3's interaction with RAD23 (HHR23A/B). Reason: The cited paper shows ataxin-3 binds the ubiquitin-like domain of the HHR23A/B (RAD23) shuttle factors, which are themselves important for nucleotide-excision repair. Ataxin-3 itself was not shown to perform NER; annotating the process to ataxin-3 from a partner's role is an over-annotation of an interaction. The underlying finding should not be lost when the process term goes - the ataxin-3-RAD23A/B ubiquitin-like-domain interaction is a real, specific molecular binding event and is the mechanistic basis of ataxin-3's documented cooperation with the proteasome shuttle factors in protein quality control. It is better represented as a binding/adaptor molecular function than as participation in NER. Supporting Evidence: PMID:10915768 important for nucleotide excision repair |
| GO:0007268 chemical synaptic transmission | TAS PMID:7655453 Trinucleotide expansion within the MJD1 gene presents clinic... | REMOVE | Summary: TAS assignment of chemical synaptic transmission citing the SCA3/MJD1 trinucleotide-expansion clinical genetics paper. Reason: The cited reference is a clinical-genetics study of the MJD1 (CAG)n expansion in German SCA families; it establishes the disease mutation, not any synaptic-transmission molecular role for ataxin-3. There is no support for this term in the cited paper at all - not weak or partial support - so REMOVE rather than MARK_AS_OVER_ANNOTATED is the right action. This is a TAS annotation, not an experimental one, so no curator judgment based on unseen full text is being second-guessed. Supporting Evidence: PMID:7655453 These results demonstrate that the MJD mutation causes the disease phenotype of most SCA patients in Germany |
| GO:0007399 nervous system development | TAS PMID:9124802 Machado-Joseph disease gene product is a cytoplasmic protein... | REMOVE | Summary: TAS assignment of nervous system development citing the ataxin-3 brain-expression paper. Reason: The cited reference documents that ataxin-3 is widely expressed throughout the brain and body and is predominantly cytoplasmic; broad expression is not evidence of a demonstrated role in nervous system development. Expression data provide no support for the term rather than partial support, so REMOVE is the correct action. This is a TAS annotation, not an experimental one, so no curator judgment based on unseen full text is being second-guessed. Supporting Evidence: PMID:9124802 expressed throughout the body and in all regions of the brain examined |
| GO:0006303 double-strand break repair via nonhomologous end joining | IMP PMID:32205441 Deficiency in classical nonhomologous end-joining-mediated r... | NEW | Summary: NEW (proposed). Wild-type ATXN3 is a regulatory component of a transcription-coupled classical non-homologous end-joining (C-NHEJ) complex, associating with RNA polymerase II, PNKP and LIG4 in a megadalton complex and with nascent RNA; ATXN3 depletion decreases error-free double-strand-break repair of transcribed genes and abrogates PNKP 3'-phosphatase activity. A further step in which ATXN3 deubiquitinates stalled RNAP II to permit resumption of transcription is the authors' proposed model, explicitly hedged in the source, and is NOT part of what this annotation asserts. Reason: This normal nuclear function of ATXN3 is not captured by any GOA annotation but is directly supported by loss-of-function experiments (PMID:32205441) and by identification of the ATXN3-containing TCR complex (PMID:30994454). It is mechanistically distinct from, and more specific than, the legacy nucleotide-excision-repair TAS annotation (GO:0006289), which was inferred only from the RAD23 interaction; the demonstrated pathway is PNKP-mediated C-NHEJ of transcribed genes. Captured as a core function via the demonstrated contribution - complex assembly with the C-NHEJ machinery and activation of PNKP - not via catalysis at the break site. The paper's RNAP II deubiquitination step is model, not result: it appears only inside "we propose a model", is called "The potential deubiquitinating role of ATXN3", and the same discussion states that "Identification and characterization of the ubiquitin ligase/deubiquitinase pair for RNAP II warrant further investigation". Supporting Evidence: PMID:32205441 ATXN3 depletion significantly decreased global transcription, repair of transcribed genes, and error-free double-strand break repair PMID:32205441 WT ATXN3 is a key regulatory component of the DSB repair complex and is pivotal in regulating both TC-NHEJ and transcription PMID:30994454 HTT forms a transcription-coupled DNA repair (TCR) complex with RNA polymerase II subunit A (POLR2A), ataxin-3, the DNA repair |
| GO:0019211 phosphatase activator activity | IMP PMID:32205441 Deficiency in classical nonhomologous end-joining-mediated r... | NEW | Summary: NEW (proposed). Wild-type ATXN3 is required for the 3'-phosphatase activity of PNKP: ATXN3 depletion or expression of polyQ-expanded ATXN3 abrogates PNKP 3'-phosphatase activity, and SCA3 patient and mouse brain extracts show significantly lower PNKP activity. ATXN3 was originally identified in the PNKP immunocomplex and the two proteins are in a common megadalton complex, so the activation is direct rather than transcriptional. Reason: This is the molecular function that the loss-of-function data in PMID:32205441 actually demonstrate for ATXN3 in transcription-coupled repair, and it is the MF assigned to the corresponding core function. It is proposed in place of asserting that ATXN3's own deubiquitinase activity is the catalytic step at the break site, which the same paper presents only as a hedged model. No GOA annotation captures the PNKP-activation role. Supporting Evidence: PMID:32205441 ATXN3-depleted or pathogenic ATXN3-expressing cells abrogate polynucleotide kinase 3′-phosphatase (PNKP) activity PMID:32205441 we demonstrated that pathogenic ATXN3 with polyQ expansion specifically impaired PNKP's 3′-phosphatase activity PMID:32205441 brain extracts from SCA3 patients and mice show significantly lower PNKP activity |
| GO:0006325 chromatin organization | IMP PMID:36971114 ATXN3 controls DNA replication and transcription by regulati... | NEW | Summary: NEW (proposed). ATXN3 regulates chromatin organization under unperturbed conditions in a catalytic (deubiquitinase)-independent manner; its loss causes abnormal nuclear/nucleolar morphology, altered DNA replication timing, increased transcription and more open chromatin, and it controls the chromatin recruitment and subcellular localization of its partner HDAC3. Reason: A distinct, deubiquitinase-independent nuclear function demonstrated by ATXN3 loss-of-function (PMID:36971114). It is not represented in the GOA set and is proposed as a non-core function; because it is explicitly catalytic-independent, it is separate from ATXN3's core DUB activity. Supporting Evidence: PMID:36971114 ATXN3 controls DNA replication and transcription by regulating chromatin PMID:36971114 Here we report the role of ATXN3 in chromatin organization during unperturbed conditions, in a catalytic-independent manner |
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Download this section (compressed HTML)Q: Which of ataxin-3's many reported roles (ERAD, proteasomal quality control, mTORC1/RHEB, autophagy/BECN1, transcription/FOXO4) reflect its evolutionarily conserved core function versus context-specific or pathological gain-of-function activities of the expanded polyQ protein?
Q: What are the physiological substrates whose ubiquitin chains ataxin-3 edits in neurons, and does substrate specificity depend on isoform (UIM3-containing vs not)?
Experiment: Define ataxin-3's endogenous linkage specificity and chain-length preference in neurons using linkage-specific Ub sensors and quantitative Ub-chain restriction assays on immunopurified endogenous ATXN3 complexes (wild-type vs catalytically dead C14A), rather than recombinant protein alone.
Experiment: Test whether the ERAD, mTORC1/RHEB, and autophagy/BECN1 activities require the same catalytic site by rescuing ATXN3-null cells with catalytically inactive and UIM-deletion mutants and scoring each pathway independently.
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