ATXN3

Machado-Joseph disease, also known as spinocerebellar ataxia-3, is an autosomal dominant neurologic disorder. The protein encoded by this gene contains (CAG)n repeats in the coding region, and the expansion of these repeats from the normal 12-44 to 52-86 is one cause of Machado-Joseph disease. There is a negative correlation between the age of onset and CAG repeat numbers.

Ataxin 3

Deubiquitinating enzyme involved in protein homeostasis maintenance, transcription, cytoskeleton regulation, myogenesis and degradation of misfolded chaperone substrates (PubMed:12297501, PubMed:17696782, PubMed:23625928, PubMed:28445460, PubMed:16118278).
Binds long polyubiquitin chains and trims them, while it has weak or no activity against chains of 4 or less ubiquitins (PubMed:17696782).
Involved in degradation of misfolded chaperone substrates via its interaction with STUB1/CHIP: recruited to monoubiquitinated STUB1/CHIP, and restricts the length of ubiquitin chain attached to STUB1/CHIP substrates and preventing further chain extension (By similarity).
Interacts with key regulators of transcription and represses transcription: acts as a histone-binding protein that regulates transcription (PubMed:12297501).
Regulates autophagy via the deubiquitination of 'Lys-402' of BECN1 leading to the stabilization of BECN1 (PubMed:28445460).

Actin cytoskeleton organization Source: MGI
Cellular response to heat Source: ParkinsonsUK-UCL
Cellular response to misfolded protein Source: UniProtKB
Chemical synaptic transmission Source: ProtInc
Intermediate filament cytoskeleton organization Source: MGI
Microtubule cytoskeleton organization Source: MGI
Monoubiquitinated protein deubiquitination Source: UniProtKB
Nervous system development Source: ProtInc
Nucleotide-excision repair Source: ProtInc
Positive regulation of ERAD pathway Source: ParkinsonsUK-UCL
Proteasome-mediated ubiquitin-dependent protein catabolic process Source: UniProtKB
Protein deubiquitination Source: ParkinsonsUK-UCL
Protein K48-linked deubiquitination Source: ParkinsonsUK-UCL
Protein K63-linked deubiquitination Source: ParkinsonsUK-UCL
Protein localization to cytosolic proteasome complex involved in ERAD pathway Source: ParkinsonsUK-UCL
Protein quality control for misfolded or incompletely synthesized proteins Source: UniProtKB
Regulation of cell-substrate adhesion Source: MGI
Ubiquitin-dependent protein catabolic process Source: ParkinsonsUK-UCL

Nucleus matrix; Nucleus. Predominantly nuclear, but not exclusively, inner nuclear matrix.

Spinocerebellar ataxia 3 (SCA3): Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to cerebellum degeneration with variable involvement of the brainstem and spinal cord. SCA3 belongs to the autosomal dominant cerebellar ataxias type I (ADCA I) which are characterized by cerebellar ataxia in combination with additional clinical features like optic atrophy, ophthalmoplegia, bulbar and extrapyramidal signs, peripheral neuropathy and dementia. The molecular defect in SCA3 is the a CAG repeat expansion in ATX3 coding region. Longer expansions result in earlier onset and more severe clinical manifestations of the disease.

Monoubiquitinated N-terminally by UBE2W, possibly leading to activate the deubiquitinating enzyme activity (PubMed:23696636).