title: HDAC6 regulates mutant SOD1 aggregation through two SMIR motifs and tubulin acetylation.
abstract: Histone deacetylase 6 (HDAC6) is a tubulin deacetylase that regulates protein aggregation and turnover. Mutations in Cu/Zn superoxide dismutase (SOD1) linked to familial amyotrophic lateral sclerosis (ALS) make the mutant protein prone to aggregation. However, the role of HDAC6 in mutant SOD1 aggregation and the ALS etiology is unclear. Here we report that HDAC6 knockdown increased mutant SOD1 aggregation in cultured cells. Different from its known role in mediating the degradation of poly-ubiquitinated proteins, HDAC6 selectively interacted with mutant SOD1 via two motifs similar to the SOD1 mutant interaction region (SMIR) that we identified previously in p62/sequestosome 1. Expression of the aggregation-prone mutant SOD1 increased α-tubulin acetylation, and the acetylation-mimicking K40Q α-tubulin mutant promoted mutant SOD1 aggregation. Our results suggest that ALS-linked mutant SOD1 can modulate HDAC6 activity and increase tubulin acetylation, which, in turn, facilitates the microtubule- and retrograde transport-dependent mutant SOD1 aggregation. HDAC6 impairment might be a common feature in various subtypes of ALS.
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Jozsef
authors.initials: J
authors.lastname: Gal
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Barnett
authors.forename: Liuqing
authors.initials: L
authors.lastname: Yang
authors.forename: Erin
authors.initials: E
authors.lastname: Brumley
authors.forename: Haining
authors.initials: H
authors.lastname: Zhu
mesh_terms: D000107:Acetylation; D020816:Amino Acid Motifs; D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D057809:HEK293 Cells; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008870:Microtubules / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020125:Mutation, Missense; D059748:Proteolysis; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D014404:Tubulin / Q000235:genetics / Q000378:metabolism*; D057149:Ubiquitinated Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C000606290:SOD1 protein, human; D014404:Tubulin; D057149:Ubiquitinated Proteins; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: Amyotrophic Lateral Sclerosis (Lou Gehrig's Disease); Cu/Zn Superoxide Dismutase (SOD1) (SOD1); Histone Deacetylase; Histone Deacetylase 6; Neurodegenerative Diseases; Protein Aggregation; Superoxide Dismutase (SOD); p62/Sequestosome 1