title: The serine protease HtrA2/Omi cleaves Parkin and irreversibly inactivates its E3 ubiquitin ligase activity.
abstract: The serine protease HtrA2 is important in regulating not only apoptosis but also cellular homeostasis. Recently, several lines of evidence suggest that HtrA2 may be intimately associated with Parkin; however, little is known about the functional relationships between HtrA2 and Parkin. Here we have shown that HtrA2 is co-localized with Parkin in the cytosol through the release of HtrA2 from the mitochondria upon cellular stresses. Moreover, endogenous levels of Parkin were significantly decreased in wild-type (HtrA2(+/+)) mouse embryonic fibroblasts (MEF) compared with those in HtrA2-knockout (HtrA2(-/-)) MEF under the same stress conditions. Using cleavage and binding assays, we have demonstrated that HtrA2 specifically binds to and directly cleaves the E3 ubiquitin (Ub) ligase Parkin. Interestingly, the HtrA2-mediated Parkin cleavage irreversibly disrupts Parkin-mediated synphilin-1 ubiquitination and autoubiquitination, indicating that HtrA2 may play a critical role in the Parkin-related pathway involved in the ubiquitin proteasome system.
authors.affiliation: School of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
authors.forename: Hye-Min
authors.initials: HM
authors.lastname: Park
authors.forename: Goo-Young
authors.initials: GY
authors.lastname: Kim
authors.forename: Min-Kyung
authors.initials: MK
authors.lastname: Nam
authors.forename: Geun-Hye
authors.initials: GH
authors.lastname: Seong
authors.forename: Chul
authors.initials: C
authors.lastname: Han
authors.forename: Kwang Chul
authors.initials: KC
authors.lastname: Chung
authors.forename: Seongman
authors.initials: S
authors.lastname: Kang
authors.forename: Hyangshuk
authors.initials: H
authors.lastname: Rhim
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D003600:Cytosol / Q000201:enzymology; D005347:Fibroblasts / Q000201:enzymology; D000074923:High-Temperature Requirement A Serine Peptidase 2; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; C498464:Sncaip protein, mouse; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D012697:Serine Endopeptidases; D000074923:High-Temperature Requirement A Serine Peptidase 2; C000615915:Htra2 protein, mouse; D046988:Proteasome Endopeptidase Complex