S-Nitrosylation of Bcl-2 Inhibits Its Ubiquitin-Proteasomal Degradation
Open accessAbstract
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.
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S-nitrosation of Bcl-2 prevents proteasomal degradation of this antiapoptotic protein after apoptotic stimuli to enhance its antiapoptotic function.
“S-nitrosation of Bcl-2 prevents the proteasomal degradation of this antiapoptotic protein after apoptotic stimuli to enhance its antiapoptotic function (21).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [21]
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- Authors
- Azad, N., Vallyathan, V., Wang, L., Tantishaiyakul, V., Stehlik, C., Leonard, S. S., & Rojanasakul, Y.
- Affiliations
- West Virginia University (US)
- National Institute for Occupational Safety and Health (US)
- Prince of Songkla University (TH)
- Corresponding author
- Rojanasakul, Yon
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2006-11
- Volume
- 281
- Issue
- 45
- Pages
- 34124-34134
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2049046201
- Cited by
- 194
- References
- 60
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 3 · 2023: 6 · 2022: 4 · 2021: 13 · 2020: 6 · 2019: 5 · 2018: 12 · 2017: 8 · 2016: 7 · 2015: 12 · 2014: 18 · 2013: 11 · 2012: 21
- FWCI
- 4.35
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL076340, R01HL076340)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- Bcl-2, S-nitrosylation, nitric oxide, ubiquitin-proteasome degradation, protein stability, apoptosis, cysteine residues, chromium(VI) toxicity, Fas ligand, buthionine sulfoximine, aminoguanidine, NONOates, sodium nitroprusside, post-translational modification
- MeSH terms
- Chromates, Flow Cytometry, Humans, Lung Neoplasms, Mutation, Nitric Oxide, Nitroso Compounds, Plasmids, Protein Processing, Post-Translational, Transfection, Ubiquitins, Blotting, Western, Mutagenesis, Site-Directed, Apoptosis, Proto-Oncogene Proteins c-bcl-2, Caspases, Immunoprecipitation, Proteasome Inhibitors
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