title: The serine protease HtrA2 cleaves UCH-L1 and inhibits its hydrolase activity: implication in the UCH-L1-mediated cell death.
abstract: Ubiquitin (Ub) carboxyl-terminal hydrolase L1 (UCH-L1) has dual functions, such as hydrolase activity on the chemical bonds formed by the C-terminal Gly of Ub and dimerization-dependent ubiquitin ligase activity. Accumulating evidence suggests that dual activities of UCH-L1 were intimately associated with Parkinson's diseases (PD) and cancer. However, the molecular mechanism that regulates UCH-L1 enzymatic activity has not yet been fully elucidated. The serine protease high temperature requirement A2 (HtrA2), a PD-associated gene, is important in regulating cell survival as well as apoptosis. Using in vitro and in vivo cleavage assays, we have demonstrated that UCH-L1 is a natural substrate for the serine protease HtrA2 in the apoptotic pathway. Notably, we show that released, cytosolic HtrA2 decreases UCH-L1 protein level and its hydrolase activity through HtrA2-mediated cleavage of UCH-L1 under apoptotic conditions. These findings suggest that the HtrA2-mediated cleavage of UCH-L1 may play important roles in regulating the fine balance between cell growth and cell death.
authors: Department of Biomedical Sciences, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea.
authors: Dae-Wook
authors: DW
authors: Park
authors: Min-Kyung
authors: MK
authors: Nam
authors: Hyangshuk
authors: H
authors: Rhim
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering; C482860:UCHL1 protein, human; D043222:Ubiquitin Thiolesterase; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2