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Papers In Press, published online ahead of print October 24, 2005
Dept. of Pharmaceutical Sciences, West Virginia University, School of Pharmacy, Morgantown, WV 26505
Corresponding Author: yrojanasakul{at}hsc.wvu.edu
Stimulation of cell surface Fas (CD95) results in recruitment of cytoplasmic proteins and activation of caspase-8, which in turn activates downstream effector caspases leading to programmed cell death. Nitric oxide (NO) plays a key role in the regulation of apoptosis, but its role in Fas-induced cell death and the underlying mechanism are largely unknown. Here we show that stimulation of the Fas receptor by its ligand (FasL) results in rapid generation of NO and concomitant decrease in cellular FLICE inhibitory protein (FLIP) expression without significant effect on Fas and Fas-associated death domain (FADD) adapter protein levels. FLIP downregulation as well as caspase-8 activation and apoptosis induced by FasL were all inhibited by the NO-liberating agent sodium nitroprusside (SNP) and DPTA NONOate, whereas the NO synthase inhibitor aminoguanidine (AG) and NO scavenger carboxy-PTIO had opposite effects, indicating an anti-apoptotic role of NO in the Fas signaling process. FasL-induced downregulation of FLIP is mediated by a ubiquitin-proteasome pathway which is negatively regulated by NO. S-nitrosylation of FLIP is an important mechanism rendering FLIP resistant to ubiquitination and proteasomal degradation by FasL. Deletion analysis shows that the caspase-like domain of FLIP is a key target for S-nitrosylation by NO and mutations of its cysteine 254 and cysteine 259 residues completely inhibit S-nitrosylation leading to increased ubiquitination and proteasomal degradation of FLIP. These findings indicate a novel pathway for NO regulation of FLIP which provides a key mechanism for apoptosis regulation and a potential new target for intervention in death receptor-associated diseases.
J. Biol. Chem, 10.1074/jbc.M510080200
Submitted on September 13, 2005
Revised on October 24, 2005
Accepted on October 24, 2005
Nitric oxide negatively regulates Fas (CD95)-induced apoptosis through inhibition of ubiquitin-proteasome mediated degradation of FLIP
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