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.
|Number of pages||6|
|Journal||Biochemical and Biophysical Research Communications|
|Publication status||Published - 2009 Sept 25|
Bibliographical noteFunding Information:
We are grateful to Dr. Julian Downward at Cancer Research UK London Research Institute for offering HtrA2 +/+ and HtrA2 −/− MEF. This work was supported by a grant of the National R&D Program for cancer control, Ministry of Health & Welfare, Republic of Korea (0720300) and the Korea Healthcare technology R&D Project, Ministry of Health, Welfare and Family Affair, Republic of Korea (A080418) and the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government (MOST) (R01-2008-000-11435-0) and Korea Research Foundation Grant funded by the Korean Government (MOEHRD, Basic Research Promotion Fund) (KRF-2007-314-C00216).
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology