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.
Pubmed ID: 17906618 RIS Download
Animals | Binding Sites | Brain | Cell Line | Enzyme Activation | Humans | MAP Kinase Kinase Kinase 3 | Mice | Mitochondrial Proteins | Models, Biological | Mutagenesis, Site-Directed | Mutation | Parkinson Disease | Phosphorylation | Protein Kinases | Serine Endopeptidases | Signal Transduction