The mitochondrial protease HtrA2 is regulated by Parkinson's disease-associated kinase PINK1
Hélène Plun-Favreau1, 5, 7, Kristina Klupsch1, 7, Nicoleta Moisoi4, Sonia Gandhi5, Svend Kjaer2, David Frith3, Kirsten Harvey6, Emma Deas5, Robert J. Harvey6, Neil McDonald2, Nicholas W. Wood5, L. Miguel Martins4 & Julian Downward1
1 Signal Transduction, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
2 Structural Biology, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
3 Protein Analysis Laboratories, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
4 Cell Death Regulation Laboratory, MRC Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK.
5 Department of Molecular Neuroscience, Institute of Neurology, and National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
6 Department of Pharmacology, The School of Pharmacy, 29/39 Brunswick Square, London WC1N 1AX, UK.
7 These authors contributed equally to this work.
Correspondence should be addressed to L. Miguel Martins lmm24@leicester.ac.uk or Julian Downward julian.downward@cancer.org.uk
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.
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