title: SARM1 and TRAF6 bind to and stabilize PINK1 on depolarized mitochondria.
abstract: Mutations in PTEN-induced putative kinase 1 (PINK1) or parkin cause autosomal recessive forms of Parkinson's disease. Recent work suggests that loss of mitochondrial membrane potential stabilizes PINK1 and that accumulated PINK1 recruits parkin from the cytoplasm to mitochondria for elimination of depolarized mitochondria, which is known as mitophagy. In this study, we find that PINK1 forms a complex with sterile α and TIR motif containing 1 (SARM1) and tumor necrosis factor receptor-associated factor 6 (TRAF6), which is important for import of PINK1 in the outer membrane and stabilization of PINK1 on depolarized mitochondria. SARM1, which is known to be an adaptor protein for Toll-like receptor, binds to PINK1 and promotes TRAF6-mediated lysine 63 chain ubiquitination of PINK1 at lysine 433. Down-regulation of SARM1 and TRAF6 abrogates accumulation of PINK1, followed by recruitment of parkin to damaged mitochondria. Some pathogenic mutations of PINK1 reduce the complex formation and ubiquitination. These results indicate that association of PINK1 with SARM1 and TRAF6 is an important step for mitophagy.
authors.affiliation: Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan Department of Life Science, Faculty of Science, Okayama University of Science, 1-1 Ridai-cho, Kita-ku, Okayama 700-0005, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Murata
authors.forename: Masakiyo
authors.initials: M
authors.lastname: Sakaguchi
authors.forename: Ken
authors.initials: K
authors.lastname: Kataoka
authors.forename: Nam-Ho
authors.initials: NH
authors.lastname: Huh
mesh_terms: D051186:Armadillo Domain Proteins / Q000737:chemistry / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008239:Lysine / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D026901:Membrane Transport Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism*; D055550:Protein Stability; D021381:Protein Transport; D011956:Receptors, Cell Surface / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination; D000099202:PTEN-Induced Putative Kinase
chemical_list: D051186:Armadillo Domain Proteins; D003598:Cytoskeletal Proteins; D008239:Lysine; D026901:Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D011494:Protein Kinases; D011956:Receptors, Cell Surface; D048029:TNF Receptor-Associated Factor 6; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C435689:SARM1 protein, human; C084008:TOMM20 protein, human; C111567:parkin protein