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ATXN3

ataxin 3
3 disorders 2 untyped 1 no genetic record 14q32.12 gene with protein product
HGNC:7106MonarchNCBI Gene 4287ENSG00000066427UniProt P54252OMIM 607047

Previous symbols: SCA3, MJD. Aliases: ATX3, JOS.

Normal function · from ai-gene-review (P54252, commit 79fe13b38970) · AI-generated, not KB evidence

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.

Cysteine-protease deubiquitinase (Josephin domain) that binds and trims long polyubiquitin chains, functioning as a ubiquitin-chain-editing enzyme in protein quality control and proteasomal/ERAD degradation; activity is stimulated by VCP/p97.
molecular function: cysteine-type deubiquitinase activity · directly involved in: protein quality control for misfolded or incompletely synthesized proteins; proteasome-mediated ubiquitin-dependent protein catabolic process · locations: cytosol; nucleus
Linkage-selective ubiquitin-chain editing: cleaves K63-linked (and K48-linked) polyubiquitin, consistent with a chain-trimming/editing DUB rather than a processive chain-disassembling DUB.
molecular function: K63-linked deubiquitinase activity · directly involved in: protein K63-linked deubiquitination
Lysosome-associated deubiquitination of the GTPase RHEB that negatively regulates mTORC1 signaling; amino acids block this ATXN3 activity, stabilizing ubiquitinated RHEB and promoting mTORC1 activation.
molecular function: cysteine-type deubiquitinase activity · directly involved in: negative regulation of TORC1 signaling · locations: lysosomal membrane
p97/VCP-associated deubiquitinase acting in ER-associated degradation (ERAD), regulating retrotranslocation of misfolded ER proteins to the cytosol for proteasomal degradation.
molecular function: cysteine-type deubiquitinase activity · directly involved in: positive regulation of ERAD pathway · locations: endoplasmic reticulum membrane
Nuclear regulatory subunit of a transcription-coupled DNA repair complex: as a component of a megadalton complex with RNA polymerase II, PNKP and LIG4, wild-type ATXN3 is required for the 3'-phosphatase activity of PNKP and associates with nascent RNA, supporting error-free, PNKP-mediated classical non-homologous end-joining of transcribed genes. The molecular function assigned here is activation of PNKP, which is what the loss-of-function and patient/mouse-brain data demonstrate. ATXN3's own deubiquitinase activity is NOT asserted as the catalytic step at the break site: the RNAP II deubiquitination event is a proposed model in PMID:32205441, explicitly hedged there, and the ubiquitin ligase/deubiquitinase pair for RNAP II is stated to warrant further investigation.
molecular function: phosphatase activator activity · directly involved in: double-strand break repair via nonhomologous end joining · locations: nucleus
In the knowledge base · computed from kb/ at build time

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.

DisorderRelationshipWhere the gene appears
Autosomal Dominant Cerebellar Ataxia Type I untyped
Representative SCA3 coding CAG/polyglutamine expansion
mechanism: Polyglutamine Proteotoxicity
Machado-Joseph Disease untyped
Pathogenic CAG trinucleotide repeat expansion in exon 10
mechanism: PolyQ-expanded ataxin-3 misfolding and nuclear aggregation
Autosomal Dominant Cerebellar Ataxia no genetic record
mechanism: Coding Polyglutamine Repeat Expansion; Expanded Polyglutamine Protein
Mechanism modules · computed from kb/

Identity from HGNC (snapshot 2026-10-01). Page layers are described in the gene pages documentation.