title: Hydrogen sulfide-linked sulfhydration of NF-κB mediates its antiapoptotic actions.
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(2)S) synthesized by cystathionine gamma-lyase (CSE). TNF-α 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-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(2)S 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.
authors.affiliation: The Solomon H Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Nilkantha
authors.initials: N
authors.lastname: Sen
authors.forename: Bindu D
authors.initials: BD
authors.lastname: Paul
authors.forename: Moataz M
authors.initials: MM
authors.lastname: Gadalla
authors.forename: Asif K
authors.initials: AK
authors.lastname: Mustafa
authors.forename: Tanusree
authors.initials: T
authors.lastname: Sen
authors.forename: Risheng
authors.initials: R
authors.lastname: Xu
authors.forename: Seyun
authors.initials: S
authors.lastname: Kim
authors.forename: Solomon H
authors.initials: SH
authors.lastname: Snyder
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D003542:Cystathionine gamma-Lyase / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D005786:Gene Expression Regulation; D006862:Hydrogen Sulfide / Q000737:chemistry*; D051379:Mice; D016328:NF-kappa B / Q000737:chemistry* / Q000502:physiology; D016329:Sp1 Transcription Factor / Q000378:metabolism; D051996:Transcription Factor RelA / Q000737:chemistry / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D016328:NF-kappa B; D016329:Sp1 Transcription Factor; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D003542:Cystathionine gamma-Lyase; D006862:Hydrogen Sulfide