The mitochondrial protease HtrA2 is regulated by Parkinson's disease-associated kinase PINK1.
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.
Plun-Favreau
Hélène
H
Signal Transduction, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
Klupsch
Kristina
K
Moisoi
Nicoleta
N
Gandhi
Sonia
S
Kjaer
Svend
S
Frith
David
D
Harvey
Kirsten
K
Deas
Emma
E
Harvey
Robert J
RJ
McDonald
Neil
N
Wood
Nicholas W
NW
Martins
L Miguel
LM
Downward
Julian
J
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
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