S-nitrosylation of XIAP impairs its anti-apoptotic function and S-nitrosylation of CK2 regulates its kinase activity and their roles in Parkinson's disease

Abstract

S-nitrosylation, a reversible post-translational modification of by adding a Nitric Oxide (NO) moiety to cysteine thiol within proteins, has been shown to involve in several neurodegenerative diseases, such as Parkinson’s Disease, through impairing the normal function of a number of proteins. X-linked inhibitor of apoptosis (XIAP) is a protein that possesses anti-apoptotic function and dysregulation of it has been linked to a number of disease such as cancers and neurodegenerative disorders. Our previous study found that NO can modify XIAP by S-nitrosylation and affect its anti-caspase activity. However, we did not identify the cysteine residue responsible for S-nitrosylation. In this study, we performed mutagenesis study and found that Cys213 of XIAP at BIR2 domain is the critical residue for XIAP S-nitrosylation and S-nitrosylation of XIAP at Cys213 impairs its anti-caspase3 activity and anti-apoptosis function. These results confirmed the importance of one critical cysteine residue (Cys213) in XIAP S-nitrosylation and S-nitrosylation-induced loss of anti-apoptotic function. CK2 is a serine/threonine protein kinase that has been implicated in a diverse array of cellular processes. CK2 has been reported to phosphorylate α-syn at Ser129. The pS129-α-syn is believed to promote its aggregation and neurotoxicity involved in the pathogenesis of PD. In this study, I found that the Cys147 of the catalytic subunit CK2a is subjected to S-nitrosylation and this modification increases its kinase activity in vitro and in cells. NO treatment enhances CK2a mediated α-syn phosphorylation and aggregation in cells. Increased S-nitrosylated CK2a and pS129-α-syn level was observed in a transgenic mice model of PD and this increase is age-dependent. NOS inhibitor L-NNA injection in mice resulted in diminished pS129-α-syn level associated with decreased S-nitrosylated CK2a suggesting CK2a S-nitrosylation may play a role in abnormal α-syn phosphorylation. My study reveals a potential novel mechanism through which nitrosative stress contributes to PD pathogenesis.

Date of Award	2016
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology