title: Ataxin-3 regulates aggresome formation of copper-zinc superoxide dismutase (SOD1) by editing K63-linked polyubiquitin chains.
abstract: Polyubiquitination of misfolded proteins, especially K63-linked polyubiquitination, is thought to be associated with the formation of inclusion bodies. However, it is not well explored whether appropriate editing of the different types of ubiquitin linkages by deubiquitinating enzymes (DUBs) affects the dynamics of inclusion bodies. In this study, we report that a specific DUB, ataxin-3, is required for the efficient recruitment of the neurodegenerative disease-associated protein copper-zinc superoxide dismutase (SOD1) to aggresomes. The overexpression of ataxin-3 promotes mutant SOD1 aggresome formation by trimming K63-linked polyubiquitin chains. Moreover, knockdown of ataxin-3 decreases mutant SOD1 aggresome formation and increases cell death induced by mutant SOD1. Thus, our data suggest that the sequestration of misfolded SOD1 into aggresomes, which is driven by ataxin-3, plays an important role in attenuating protein misfolding-induced cell toxicity.
authors: Laboratory of Molecular Neuropathology, Department of Pharmacology, Soochow University College of Pharmaceutical Sciences, Suzhou, Jiangsu 215123, China.
authors: Hongfeng
authors: H
authors: Wang
authors: Zheng
authors: Z
authors: Ying
authors: Guanghui
authors: G
authors: Wang
mesh_terms: D000818:Animals; D000067699:Ataxin-3; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; C000606290:SOD1 protein, human; D014157:Transcription Factors; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C092341:ATXN3 protein, human; D000067699:Ataxin-3; C511594:Atxn3 protein, mouse