The serine protease HtrA2/Omi cleaves Parkin and irreversibly inactivates its E3 ubiquitin ligase activity.
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.
Park
Hye-Min
HM
School of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
Kim
Goo-Young
GY
Nam
Min-Kyung
MK
Seong
Geun-Hye
GH
Han
Chul
C
Chung
Kwang Chul
KC
Kang
Seongman
S
Rhim
Hyangshuk
H
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
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