Hydrogen sulfide-linked sulfhydration of NF-?B mediates its antiapoptotic actions.

ABSTRACT: Nuclear factor ?B (NF-?B) is an antiapoptotic transcription factor. We show that the antiapoptotic actions of NF-?B are mediated by hydrogen sulfide (H(2)S) synthesized by cystathionine gamma-lyase (CSE). TNF-? treatment triples H(2)S generation by stimulating binding of SP1 to the CSE promoter. H(2)S generated by CSE stimulates DNA binding and gene activation of NF-?B, 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(2)S acts by sulfhydrating the p65 subunit of NF-?B at cysteine-38, which promotes its binding to the coactivator ribosomal protein S3 (RPS3). Sulfhydration of p65 predominates early after TNF-? treatment, then declines and is succeeded by a reciprocal enhancement of p65 nitrosylation. In CSE mutant mice, antiapoptotic influences of NF-?B are markedly diminished. Thus, sulfhydration of NF-?B appears to be a physiologic determinant of its antiapoptotic transcriptional activity.

SUBMITTER: Sen N 

PROVIDER: S-EPMC3261430 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature