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FLASH GENE

Symbol

ATXN3

contributors: mct/pgu - updated : 27-06-2018

HGNC name	ataxin 3
HGNC id	7106

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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
EC.number	3.1.2.15

DNA

TYPE	functioning gene
STRUCTURE	48.07 kb     11 Exon(s)

regulatory sequence	Promoter (CAAT box)
	cytosine-phosphate-guanine/HTF
	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

RNA

TRANSCRIPTS	type	messenger

text	at least four isoforms due to alternative stop codon usage and unique aminoacid substitutions (PMID: 9804376)

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_004993 11 - 6293 NP_004984 - 361 - 2009 19935829 reference isoform NM_001164782 - polyA site 6075 NP_001158254 - 33 - 2009 19935829 isoform ae NM_001164781 - - 6713 NP_001158253 - 291 - 2009 19935829 isoform y NM_030660 10 - 6758 NP_109376 - 306 - 2009 19935829 isoform h NM_001164780 - - 6627 NP_001158252 - 182 - 2009 19935829 isoform u NM_001164779 - - 6560 NP_001158251 - 240 - 2009 19935829 isoform r NM_001164778 - - 6438 NP_001158250 - 154 - 2009 19935829 isoform o NM_001164777 - - 6120 NP_001158249 - 48 - 2009 19935829 isoform j NM_001164776 - - 6285 NP_001158248 - 103 - 2009 19935829 isoform g NM_001164775 - - 6339 NP_001158247 - 120 - 2009 19935829 isoform c NM_001164774 - - 6240 NP_001158246 - 88 - 2009 19935829 isoform b NM_001127697 8 - 6770 NP_001121169 - 310 - 2009 19935829 isoform e NM_001127696 10 - 6878 NP_001121168 - 346 - 2009 19935829 isoform ad

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive liver       highly Endocrine pancreas       highly Nervous brain basal nuclei striatum     Respiratory lung       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Blood / Hematopoietic bone marrow       Connective bone       Epithelial secretory glandular endocrine   Epithelial secretory glandular exocrine   Muscular striatum skeletal     Nervous central       Nervous peripherous

cells

System Cell Pubmed Species Stage Rna symbol Nervous neuron

cell lineage
cell lines	lymphoblastoid cells
fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	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

HOMOLOGY

interspecies	ortholog to rattus Atxn3
	ortholog to murine Mjd

Homologene

FAMILY

CATEGORY

enzyme , regulatory , signaling neurotransmitter

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm
	intracellular,nucleus,nucleoplasm
text	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

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component

component of the ubiquitin proteasome system

INTERACTION

DNA

RNA

small molecule

protein	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

REGULATION

Other

regulated by CSNK2A1 (CSNK2A1-dependent phosphorylation controls nuclear localization, inclusion formation and stability of ATXN3)

ASSOCIATED DISORDERS

corresponding disease(s)

MJD

Susceptibility

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)
Marker
Therapy target
	System Type Disorder Pubmed neurology ataxia   potential therapeutic role of ataxin-3 activity for polyglutamine disorders neurology ataxia   target for therapeutic by ribosome-interacting drugs (to fight the toxicity of polyalanine-frameshifted peptides) cancer     targeting ATXN3 may be a promising strategy to radio-sensitise BRCA-deficient cancers

ANIMAL & CELL MODELS