title: Dysferlin interacts with histone deacetylase 6 and increases alpha-tubulin acetylation.
abstract: Dysferlin is a multi-C2 domain transmembrane protein involved in a plethora of cellular functions, most notably in skeletal muscle membrane repair, but also in myogenesis, cellular adhesion and intercellular calcium signaling. We previously showed that dysferlin interacts with alpha-tubulin and microtubules in muscle cells. Microtubules are heavily reorganized during myogenesis to sustain growth and elongation of the nascent muscle fiber. Microtubule function is regulated by post-translational modifications, such as acetylation of its alpha-tubulin subunit, which is modulated by the histone deacetylase 6 (HDAC6) enzyme. In this study, we identified HDAC6 as a novel dysferlin-binding partner. Dysferlin prevents HDAC6 from deacetylating alpha-tubulin by physically binding to both the enzyme, via its C2D domain, and to the substrate, alpha-tubulin, via its C2A and C2B domains. We further show that dysferlin expression promotes alpha-tubulin acetylation, as well as increased microtubule resistance to, and recovery from, Nocodazole- and cold-induced depolymerization. By selectively inhibiting HDAC6 using Tubastatin A, we demonstrate that myotube formation was impaired when alpha-tubulin was hyperacetylated early in the myogenic process; however, myotube elongation occurred when alpha-tubulin was hyperacetylated in myotubes. This study suggests a novel role for dysferlin in myogenesis and identifies HDAC6 as a novel dysferlin-interacting protein.
authors.affiliation: Neuromuscular Research Group, Departments of Neurology and Biomedicine, University, Hospital, Basel, Switzerland.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Di Fulvio
authors.forename: Bilal A
authors.initials: BA
authors.lastname: Azakir
authors.forename: Christian
authors.initials: C
authors.lastname: Therrien
authors.forename: Michael
authors.initials: M
authors.lastname: Sinnreich
mesh_terms: D000107:Acetylation; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D000073939:Dysferlin; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D024510:Muscle Development; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000201:enzymology; D009124:Muscle Proteins / Q000737:chemistry / Q000378:metabolism*; D058105:Polymerization; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D014404:Tubulin / Q000378:metabolism*
chemical_list: C114839:DYSF protein, human; C497505:Dysf protein, mouse; D000073939:Dysferlin; D008565:Membrane Proteins; D009124:Muscle Proteins; D014404:Tubulin; C433811:HDAC6 protein, human; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases