After exposure to inflammatory signals, activation of the transcription factor NF-κB is needed to upregulate expression of antiapoptotic genes that confer cell survival. In Molecular Cell, Sen et al. show that TNF transiently upregulates expression of cystathionine γ-lysase (CSE), producing hydrogen sulfide (H2S) that then modifies Cys38 of NF-κB (subunit p65) to create a hydropersulfide (–SSH). Sulfhydration of Cys38 increases the DNA-binding activity of p65 and expression of the antiapoptotic factor Bcl-xL, the deubiquitinase A20, the ubiquitin ligase cIAP2 and the apoptosis inhibitor XIAP. Higher expression of genes encoding prosurvival molecules is linked to more association of p65 with its cofactor, ribosome protein S3 (RPS3). At later time points, p65 is nitrosylated at Cys38, which blunts both its ability to interact with RPS3 and its DNA-binding activity. Inhibition of CSE, substitution of p65 Cys38 or knockdown of RPS3 in TNF-stimulated cells leads to lower expression of genes encoding prosurvival molecules and more cell apoptosis. These findings demonstrate the importance of the interaction of p65 with RPS3 for cell survival and provide insight into how their association is regulated.

Mol. Cell 45, 13–24 (2012)