title: The mitochondrial protease HtrA2 is regulated by Parkinson's disease-associated kinase PINK1.
abstract: In mice, targeted deletion of the serine protease HtrA2 (also known as Omi) causes mitochondrial dysfunction leading to a neurodegenerative disorder with parkinsonian features. In humans, point mutations in HtrA2 are a susceptibility factor for Parkinson's disease (PARK13 locus). Mutations in PINK1, a putative mitochondrial protein kinase, are associated with the PARK6 autosomal recessive locus for susceptibility to early-onset Parkinson's disease. Here we determine that HtrA2 interacts with PINK1 and that both are components of the same stress-sensing pathway. HtrA2 is phosphorylated on activation of the p38 pathway, occurring in a PINK1-dependent manner at a residue adjacent to a position found mutated in patients with Parkinson's disease. HtrA2 phosphorylation is decreased in brains of patients with Parkinson's disease carrying mutations in PINK1. We suggest that PINK1-dependent phosphorylation of HtrA2 might modulate its proteolytic activity, thereby contributing to an increased resistance of cells to mitochondrial stress.
authors: Signal Transduction, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
authors: Hélène
authors: H
authors: Plun-Favreau
authors: Kristina
authors: K
authors: Klupsch
authors: Nicoleta
authors: N
authors: Moisoi
authors: Sonia
authors: S
authors: Gandhi
authors: Svend
authors: S
authors: Kjaer
authors: David
authors: D
authors: Frith
authors: Kirsten
authors: K
authors: Harvey
authors: Emma
authors: E
authors: Deas
authors: Robert J
authors: RJ
authors: Harvey
authors: Neil
authors: N
authors: McDonald
authors: Nicholas W
authors: NW
authors: Wood
authors: L Miguel
authors: LM
authors: Martins
authors: Julian
authors: J
authors: Downward
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001921:Brain / Q000473:pathology; D002460:Cell Line; D004789:Enzyme Activation / Q000235:genetics; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D048748:MAP Kinase Kinase Kinase 3 / Q000378:metabolism; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics / Q000502:physiology*; D008954:Models, Biological; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010300:Parkinson Disease / Q000209:etiology*; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology*; D012697:Serine Endopeptidases / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D000099202:PTEN-Induced Putative Kinase
chemical_list: D000074923:High-Temperature Requirement A Serine Peptidase 2; D048748:MAP Kinase Kinase Kinase 3; D024101:Mitochondrial Proteins; D011494:Protein Kinases; D012697:Serine Endopeptidases; D000099202:PTEN-Induced Putative Kinase; C482625:MAP3K3 protein, human; C000615914:HTRA2 protein, human; C000615915:Htra2 protein, mouse