The serine protease HtrA2 cleaves UCH-L1 and inhibits its hydrolase activity: Implication in the UCH-L1-mediated cell death

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.

► UCH-L1 inactivation caused toxicity in UCH-L1-positive cancer cells.
► Upon cell death, HtrA2 was colocalized with UCH-L1 in the cytosol.
► HtrA2 directly cleaves UCH-L1 in a serine protease activity-dependent manner.
► The HtrA2-mediated cleavage of UCH-L1 impaired hydrolase activity of UCH-L1.
► HtrA2 may be a critical regulatory factor for UCH-L1-mediated cell death.