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Symbol ATXN3 contributors: mct/pgu - updated : 27-06-2018
HGNC name ataxin 3
HGNC id 7106
Corresponding disease
MJD Machado-Joseph disease
Location 14q32.12      Physical location : 92.524.896 - 92.572.965
Synonym name
  • josephin
  • Machado-Joseph disease protein 1
  • Synonym symbol(s) ATX3, SCA3, JOS, AT3, josephin
    TYPE functioning gene
    STRUCTURE 48.07 kb     11 Exon(s)
    regulatory sequence Promoter (CAAT box)
    Binding site
    motif repetitive sequence   triplet
    text structure
  • 13 to 36 CAG repeats
  • 5'-flanking region included a TATA-less promoter with GC-rich regions, a CCAAT box and multiple potential SP1 binding sites
  • MAPPING cloned Y linked   status confirmed
    TRANSCRIPTS type messenger
    text at least four isoforms due to alternative stop codon usage and unique aminoacid substitutions (PMID: 9804376)
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    11 - 6293 - 361 - 2009 19935829
    reference isoform
    - polyA site 6075 - 33 - 2009 19935829
    isoform ae
    - - 6713 - 291 - 2009 19935829
    isoform y
    10 - 6758 - 306 - 2009 19935829
    isoform h
    - - 6627 - 182 - 2009 19935829
    isoform u
    - - 6560 - 240 - 2009 19935829
    isoform r
    - - 6438 - 154 - 2009 19935829
    isoform o
    - - 6120 - 48 - 2009 19935829
    isoform j
    - - 6285 - 103 - 2009 19935829
    isoform g
    - - 6339 - 120 - 2009 19935829
    isoform c
    - - 6240 - 88 - 2009 19935829
    isoform b
    8 - 6770 - 310 - 2009 19935829
    isoform e
    10 - 6878 - 346 - 2009 19935829
    isoform ad
    Type widely
       expressed in (based on citations)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveliver   highly
    Endocrinepancreas   highly
    Nervousbrainbasal nucleistriatum  
    Respiratorylung   highly
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Blood / Hematopoieticbone marrow   
    SystemCellPubmedSpeciesStageRna symbol
    cell lineage
    cell lines lymphoblastoid cells
    at STAGE
  • structured N-terminal Josephin domain (JD) , folded N-terminal domain (Josephin domain, residues 1-182)
  • nuclear localization signal (NLS) close to the glutamine tract
  • two ubiquitin-interacting motifs that bind polyubiquilated proteins with a strong preference for chains containing four or more ubiquitins and a polyQ-tract, two contiguous but distinct ubiquitin-binding sites
  • a central flexible region (residues 183-291), a poly-glutamine sequence of variable length
  • C-terminal polyglutamine-containing domain (a polyglutamine stretch encoded by 13 to 36 CAG repeats), inhibiting coactivator-dependent transcription and required for binding coactivators, short C-terminal flexible region
  • mono polymer heteromer
    interspecies ortholog to rattus Atxn3
    ortholog to murine Mjd
    CATEGORY enzyme , regulatory , signaling neurotransmitter
    SUBCELLULAR LOCALIZATION     intracellular
  • translocation in the nucleus for formation of intranuclear inclusions (Marinesco body)
  • upon oxidative stress, ATXN3 and FOXO4 translocate to the nucleus
  • basic FUNCTION
  • cysteine-protease associated factor conferring a higher susceptibility to death on cells in the Golgi phase
  • inducing cell death and formation of intranuclear inclusions in neuronal cells
  • playing a role in ubiquitin-dependent pathways and in transcriptional activation
  • histone-binding with two independent transcriptional corepressor activities, transcriptional regulation involving targeting histones, coactivators, and an independent mode of direct repression of transcription
  • monomeric domain which folds into a globular conformation and possesses ubiquitin protease activity
  • involved in regulation of the endoplasmic reticulum-associated degradation pathway by modulating VCP-dependent extraction of proteins from the ER
  • polyubiquitin binding protein with ubiquitin protease activity and is a striking suppressor of polyglutamine neurodegeneration
  • having autoproteolytic activity, sustained by the same residues responsible for the ubiquitin hydrolase activity (autolytic activity may play a role in pathogenesis, as fragments carrying expanded polyglutamines are thought to be significantly more toxic than the whole protein)
  • cleaves ubiquitin chains through its Josephin domain and binds ubiquitin chains through a C-terminal cluster of ubiquitin interaction motifs neighboring the pathogenic polyglutamine tract
  • deubiquitinating enzymes that edits topologically complex chains
  • displays deneddylase activity against a fluorogenic NEDD8 substrate
  • Josephin domain-containing proteins is a novel family of active de-ubiquitination enzymes with wide phylogenic distribution
  • key role of CSNK2A1-mediated phosphorylation of ATXN3 in MJD pathophysiology
  • acts as a polyubiquitin-binding protein, recruiting poly-ubiquitinated substrates through a carboxy-terminal cluster of ubiquitin interaction motifs
  • cleaves ubiquitin chains through its Josephin domain and thereby facilitates proteasomal degradation
  • plays an important role in regulating the FOXO4-dependent antioxidant stress response via SOD2,suggesting that a decreased antioxidative capacity and increased susceptibility towards oxidative stress contributes to neuronal cell death in MJD
  • UBE2W and ATXN3, participate in initiating, regulating, and terminating the STUB1 ubiquitination cycle
  • potential role of ATXN3 cleavage by calpains in the pathogenesis of MJD
  • plays an important role in regulating the BL2L1-BAX-mediated anti-oxidative response by modulating the interaction between BCL2L1 and BAX
    a component
  • component of the ubiquitin proteasome system
    small molecule
  • interaction of normal and mutant MJD with the UBL domain of RAD23A, RAD23B
  • VCP through its polyglutamine domain (binding is modulated by the size of the polyglutamine tract)
  • interacting with the major histone acetyltransferases cAMP-response-element binding protein (CREB)-binding protein, p300, and p300/CREB-binding protein-associated factor
  • specific binding of nuclear proteins to the putative core promoter region
  • interacting with UBE4B (thereby mediated its polyubiquitylation)
  • interacts with ubiquitin-proteasome pathway components
  • PSMC5 plays an important role in regulating ataxin-3 degradation by the proteasome
  • molecular interaction between wild-type ataxin-3 and NEDD8
  • functional interaction between ATXN3 and PARK2 (both wild-type and polyQ-expanded mutant ataxin-3 can deubiquitinate parkin, regardless of the lysine residue used to assemble poly-Ub chains) (
  • interacts with the forkhead box O (FOXO) transcription factor FOXO4 and activates the FOXO4-dependent transcription of the manganese superoxide dismutase (SOD2) gene
  • in the nucleus, concomitantly bind to the SOD2 gene promoter and increase the expression of the antioxidant enzyme SOD2
  • opposes PARK2 ubiquitination by regulating the E2 ubiquitin-conjugating enzyme
  • key role of calpain in ATXN3 aggregation, but ggregate formation was dependent on functional Na+ and K+ channels as well as ionotropic and voltage-gated Ca2+ channels
  • required for the efficient recruitment of the neurodegenerative disease-associated protein copper-zinc superoxide dismutase (SOD1) to aggresomes
  • VCP was shown to be an activator specifically of wild-type ATXN3, exhibiting no effect on expanded ATXN3
  • is a substrate of CAPN1 and CAPN2 and these proteases present promising targets for therapeutic intervention
  • plays a protective role against cellular oxidative stress induced by H2O2 in a BCL2L1-dependent manner
  • promotes the interaction between BCL2L1 and BAX, but does not affect the ubiquitination and degradation of BCL2L1
  • VCP-ATXN3 complex is the essential machinery for regulation of RNF8 homeostasis under both physiological and genotoxic conditions
  • VCP stabilizes BECN1 levels by promoting the deubiquitinase activity of ATXN3 towards BECN1
  • cell & other
    Other regulated by CSNK2A1 (CSNK2A1-dependent phosphorylation controls nuclear localization, inclusion formation and stability of ATXN3)
    corresponding disease(s) MJD
    Variant & Polymorphism other no evidence for an instability predisposing haplotype due to the stretch of polyglutamine
    Candidate gene for therapeutic by ribosome-interacting drugs (to fight the toxicity of polyalanine-frameshifted peptides)
    Therapy target
    potential therapeutic role of ataxin-3 activity for polyglutamine disorders
    target for therapeutic by ribosome-interacting drugs (to fight the toxicity of polyalanine-frameshifted peptides)
    targeting ATXN3 may be a promising strategy to radio-sensitise BRCA-deficient cancers