title: PINK1 phosphorylates transglutaminase 2 and blocks its proteasomal degradation.
abstract: Parkinson's disease (PD) is characterized by progressive dopaminergic neuronal loss and the formation of abnormal protein aggregates, referred to as Lewy bodies (LBs). PINK1 is a serine/threonine protein kinase that protects cells from stress-induced mitochondrial dysfunction. PINK1 gene mutations cause one form of autosomal recessive early-onset PD. Transglutaminase 2 (TG2) is an intracellular protein cross-linking enzyme that has an important role in LB formation during PD pathogenesis. This study identifies PINK1 as a novel TG2 binding partner and shows that PINK1 stabilizes the half-life of TG2 via inhibition of TG2 ubiquitination and subsequent proteasomal degradation. PINK1 affects TG2 stability in a kinase-dependent manner. In addition, PINK1 directly phosphorylates TG2 in carbonyl cyanide m-chlorophenyl hydrazine-induced mitochondrial damaged states, thereby enhancing TG2 accumulation and intracellular protein cross-linking products. This study further confirms the functional link between upstream PINK1 and downstream TG2 in Drosophila melanogaster. These data suggest that PINK1 positively regulates TG2 activity, which may be closely associated with aggresome formation in neuronal cells.
authors.affiliation: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
authors.forename: Boram
authors.initials: B
authors.lastname: Min
authors.forename: Young-Chang
authors.initials: YC
authors.lastname: Kwon
authors.forename: Kwang-Min
authors.initials: KM
authors.lastname: Choe
authors.forename: Kwang Chul
authors.initials: KC
authors.lastname: Chung
mesh_terms: D000818:Animals; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D002460:Cell Line; D004331:Drosophila melanogaster; D004789:Enzyme Activation / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008822:Mice, Transgenic; D015388:Organelles / Q000378:metabolism; D017354:Point Mutation / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000502:physiology; D061209:Proton Ionophores / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D014162:Transfection; D011503:Transglutaminases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects / Q000235:genetics; D000099202:PTEN-Induced Putative Kinase
chemical_list: D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D019204:GTP-Binding Proteins; D046988:Proteasome Endopeptidase Complex; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011494:Protein Kinases; D061209:Proton Ionophores; D012333:RNA, Messenger; D011503:Transglutaminases; D000099202:PTEN-Induced Putative Kinase
keywords: PINK1; Parkinson's disease; phosphorylation; transglutaminase 2; ubiquitination