Hydrogen Sulfide-Linked Sulfhydration of NF-κB Mediates Its Antiapoptotic Actions

• Published in: Molecular cell 2012-01, Vol.45 (1), p.13-24
• Main Authors: Sen, Nilkantha, Paul, Bindu D., Gadalla, Moataz M., Mustafa, Asif K., Sen, Tanusree, Xu, Risheng, Kim, Seyun, Snyder, Solomon H.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - physiology; cystathionine; cystathionine gamma-lyase; Cystathionine gamma-Lyase - genetics; Cystathionine gamma-Lyase - metabolism; Cystathionine gamma-Lyase - physiology; DNA; gene activation; Gene Expression Regulation; glutathione; hydrogen sulfide; Hydrogen Sulfide - chemistry; Mice; mutants; NF-kappa B - chemistry; NF-kappa B - physiology; oxidative stress; Sp1 Transcription Factor - metabolism; transcription (genetics); transcription factor NF-kappa B; Transcription Factor RelA - chemistry; Transcription Factor RelA - metabolism; tumor necrosis factor-alpha; Tumor Necrosis Factor-alpha - physiology
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2011.10.021

Nuclear factor κB (NF-κB) is an antiapoptotic transcription factor. We show that the antiapoptotic actions of NF-κB are mediated by hydrogen sulfide (H2S) synthesized by cystathionine gamma-lyase (CSE). TNF-α treatment triples H2S generation by stimulating binding of SP1 to the CSE promoter. H2S 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. H2S 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. [Display omitted] ► TNF-α stimulates transcription of the H2S generating enzyme CSE ► The synthesized H2S sulfhydrates the p65 subunit of NF-κB at cysteine-38 ► Sulfhydration of p65 augments its ability to bind its coactivator RPS3 ► The activator complex then stimulates transcription of antiapoptotic genes