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Ubiquitination of the polyglutamine disease protein ataxin‐3 enhances its activity as a deubiquitinating enzyme
Author(s) -
Todi Sokol V,
Winborn Brett J,
Williams Aislinn J,
Paulson Henry L
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1026.1
Subject(s) - deubiquitinating enzyme , ubiquitin , polyglutamine tract , microbiology and biotechnology , chemistry , lysine , biology , biochemistry , amino acid , gene , mutant , huntingtin
Protein ubiquitination regulates a broad spectrum of cellular functions. Diverse ubiquitin ligases and deubiquitinating enzymes (DUBs) control the ubiquitination state of, and types of ubiquitin chains attached to, various proteins. Ataxin‐3 (AT3) is a DUB with a polyglutamine tract which, when expanded, causes the neurodegenerative disorder Spinocerebellar Ataxia Type 3. Disease pathogenesis in expanded polyglutamine disorders is greatly influenced by the disease protein context and function, therefore understanding normal properties of AT3 is important. Previous data from our laboratory and others revealed that AT3 functions in protein quality control. Here we provide evidence that AT3 ubiquitination enhances its DUB activity. In cells, endogenous AT3 ubiquitination is increased by the presence of excess ubiquitin chains, suggesting that AT3 ubiquitination is linked to cellular ubiquitin levels. Ubiquitinated AT3 (AT3‐ub) cleaves lysine(K)‐63 hexaubiquitin chains more efficiently than does unmodified AT3. Similar to unmodified AT3, AT3‐ub preferentially cleaves K‐63 linked ubiquitin over K‐48 chains, and longer over shorter chains. Collectively our findings suggest that ubiquitination of AT3 and the corresponding enhancement of its DUB activity are important to cells in which protein homeostasis is impaired. This work was supported by: NRSA NS056609 (AJW), R01 NS038712 (HLP).