S-nitrosylation, a reversible post-translational modification of proteins by adding a nitric oxide (NO) adduct on the thiol group of cystine residue, has recently been shown to involve in several neurodegenerative diseases such as Pakinson’s Disease (PD) through modifying several important prosurvival molecules and thereby impairing their protective functions. In present study, we demonstrated that the protective function of XIAP, a potent anti-apoptotic protein that can directly inhibit activated caspases, was compromised by S-nitrosylation which might contribute to pathogenesis of PD....[ Read more ]

S-nitrosylation, a reversible post-translational modification of proteins by adding a nitric oxide (NO) adduct on the thiol group of cystine residue, has recently been shown to involve in several neurodegenerative diseases such as Pakinson’s Disease (PD) through modifying several important prosurvival molecules and thereby impairing their protective functions. In present study, we demonstrated that the protective function of XIAP, a potent anti-apoptotic protein that can directly inhibit activated caspases, was compromised by S-nitrosylation which might contribute to pathogenesis of PD.

We first showed that XIAP was subject to S-nitrosylation in vitro by NO donor and ex vivo by endogenous NO source. This modification occurred on XIAP BIR domains but not RING domains. We then demonstrated that this modification compromised XIAP protective function in cell-based PD models. We further showed that NO compromises XIAP protective function through impairing XIAP anti-caspase 3 capability. We also identified multiple targeting cysteine residues that may account for XIAP S-nitrosylation by mass spectrometry.

Taken together, this study suggests a novel molecular pathway linking nitrosative stress to the pathogenesis of PD.