title: Drosophila HtrA2 is dispensable for apoptosis but acts downstream of PINK1 independently from Parkin.
abstract: High temperature requirement A2 (HtrA2/Omi) is a mitochondrial protease that exhibits proapoptotic and cell-protective properties and has been linked to Parkinson's disease (PD). Impaired mitochondrial function is a common trait in PD patients, and is likely to play a significant role in pathogenesis of parkinsonism, but the molecular mechanisms remain poorly understood. Genetic studies in Drosophila have provided valuable insight into the function of other PD-linked genes, in particular PINK1 and parkin, and their role in maintaining mitochondrial integrity. Recently, HtrA2 was shown to be phosphorylated in a PINK1-dependent manner, suggesting it might act in the PINK1 pathway. Here, we describe the characterization of mutations in Drosophila HtrA2, and genetic analysis of its function with PINK1 and parkin. Interestingly, we find HtrA2 appears to be dispensable for developmental or stress-induced apoptosis. In addition, we found HtrA2 mutants share some phenotypic similarities with parkin and PINK1 mutants, suggesting that it may function in maintaining mitochondrial integrity. Our genetic interaction studies, including analysis of double-mutant combinations and epistasis experiments, suggest HtrA2 acts downstream of PINK1 but in a pathway parallel to Parkin.
authors.affiliation: MRC Centre for Developmental and Biomedical Genetics, University of Sheffield, Sheffield, UK.
authors.forename: L S
authors.initials: LS
authors.lastname: Tain
authors.forename: R B
authors.initials: RB
authors.lastname: Chowdhury
authors.forename: R N
authors.initials: RN
authors.lastname: Tao
authors.forename: H
authors.initials: H
authors.lastname: Plun-Favreau
authors.forename: N
authors.initials: N
authors.lastname: Moisoi
authors.forename: L M
authors.initials: LM
authors.lastname: Martins
authors.forename: J
authors.initials: J
authors.lastname: Downward
authors.forename: A J
authors.initials: AJ
authors.lastname: Whitworth
authors.forename: N
authors.initials: N
authors.lastname: Tapon
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000831:Animals, Newborn; D017209:Apoptosis; D004330:Drosophila / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005298:Fertility / Q000235:genetics; D000074923:High-Temperature Requirement A Serine Peptidase 2; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase
chemical_list: D029721:Drosophila Proteins; D000074923:High-Temperature Requirement A Serine Peptidase 2; D050505:Mutant Proteins; D017346:Protein Serine-Threonine Kinases; D012697:Serine Endopeptidases; D044767:Ubiquitin-Protein Ligases; C534484:PINK1 protein, Drosophila; D000099202:PTEN-Induced Putative Kinase; C530280:HtrA2 protein, Drosophila; C487430:park protein, Drosophila