Hydrogen sulfide-linked sulfhydration of NF-κB mediates its antiapoptotic actions

Nilkantha Sen, Bindu D. Paul, Moataz M. Gadalla, Asif K. Mustafa, Tanusree Sen, Risheng Xu, Seyun Kim, Solomon H. Snyder

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366 Scopus citations

Abstract

Nuclear factor κB (NF-κB) is an antiapoptotic transcription factor. We show that the antiapoptotic actions of NF-κB are mediated by hydrogen sulfide (H 2S) synthesized by cystathionine gamma-lyase (CSE). TNF-α treatment triples H 2S generation by stimulating binding of SP1 to the CSE promoter. H 2S generated by CSE stimulates DNA binding and gene activation of NF-κB, processes that are abolished in CSE-deleted mice. As CSE deletion leads to decreased glutathione levels, resultant oxidative stress may contribute to alterations in CSE mutant mice. H 2S acts by sulfhydrating the p65 subunit of NF-κB at cysteine-38, which promotes its binding to the coactivator ribosomal protein S3 (RPS3). Sulfhydration of p65 predominates early after TNF-α treatment, then declines and is succeeded by a reciprocal enhancement of p65 nitrosylation. In CSE mutant mice, antiapoptotic influences of NF-κB are markedly diminished. Thus, sulfhydration of NF-κB appears to be a physiologic determinant of its antiapoptotic transcriptional activity.

Original languageEnglish (US)
Pages (from-to)13-24
Number of pages12
JournalMolecular Cell
Volume45
Issue number1
DOIs
StatePublished - Jan 13 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Sen, N., Paul, B. D., Gadalla, M. M., Mustafa, A. K., Sen, T., Xu, R., Kim, S., & Snyder, S. H. (2012). Hydrogen sulfide-linked sulfhydration of NF-κB mediates its antiapoptotic actions. Molecular Cell, 45(1), 13-24. https://doi.org/10.1016/j.molcel.2011.10.021