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J. Biol. Chem., Vol. 281, Issue 45, 34124-34134, November 10, 2006

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S-Nitrosylation of Bcl-2 Inhibits Its Ubiquitin-Proteasomal Degradation

A NOVEL ANTIAPOPTOTIC MECHANISM THAT SUPPRESSES APOPTOSIS^*

Neelam Azad, Val Vallyathan, Liying Wang, Vimon Tantishaiyakul^¶, Christian Stehlik^||, Stephen S. Leonard, and Yon Rojanasakul¹

From the Department of Pharmaceutical Sciences and ^||Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia 26506, the Pathology and Physiology Research Branch, National Institute for Occupational, Safety and Health, Morgantown, West Virginia 26505, and the ^¶Department of Pharmaceutical Chemistry, Songkla University, Songkla 90110, Thailand

Bcl-2 is a key apoptosis regulatory protein of the mitochondrial death pathway whose function is dependent on its expression levels. Although Bcl-2 expression is controlled by various mechanisms, post-translational modifications, such as ubiquitination and proteasomal degradation, have emerged as important regulators of Bcl-2 function. However, the underlying mechanisms of this regulation are unclear. We report here that Bcl-2 undergoes S-nitrosylation by endogenous nitric oxide (NO) in response to multiple apoptotic mediators and that this modification inhibits ubiquitin-proteasomal degradation of Bcl-2. Inhibition of NO production by the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide and by NO synthase inhibitor aminoguanidine effectively inhibited S-nitrosylation of Bcl-2, increased its ubiquitination, and promoted apoptotic cell death induced by chromium (VI). In contrast, the NO donors dipropylenetriamine NONOate and sodium nitroprusside showed opposite effects. The effect of NO on Bcl-2 stability was shown to be independent of its dephosphorylation. Mutational analysis of Bcl-2 further showed that the two cysteine residues of Bcl-2 (Cys¹⁵⁸ and Cys²²⁹) are important in the S-nitrosylation process and that mutations of these cysteines completely inhibited Bcl-2 S-nitrosylation. Treatment of the cells with other stress inducers, including Fas ligand and buthionine sulfoxide, also induced Bcl-2 S-nitrosylation, suggesting that this is a general phenomenon that regulates Bcl-2 stability and function under various stress conditions. These findings indicate a novel function of NO and its regulation of Bcl-2, which provides a key mechanism for the control of apoptotic cell death and cancer development.

Received for publication, March 17, 2006 , and in revised form, September 14, 2006.

^* This work was supported by National Institutes of Health Grant HL076340. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Pharmaceutical Sciences, West Virginia University, P.O. Box 9530, Morgantown, WV 26506. E-mail: yrojanasakul{at}hsc.wvu.edu.

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