S-nitrosylation: Physiological regulation of NF-κB

Aspate of recent discoveries indicates that the study of protein S-nitrosylation is rapidly leaving its salad days behind. S-nitrosylation, the formation of S -nitrosothiol (SNO) by covalent addition to cysteine (Cys) residues of a nitric oxide (NO) moiety (formally as NO+), has been shown to regulate in intact cells the function of a broad spectrum of proteins (1). Important recent findings include demonstrations of major roles for S-nitrosylation in vesicle-mediated insulin release (2), in protein processing associated with the neurodegeneration of Parkinson's disease (3), and in the essential mechanisms of vectorial membrane trafficking (4). In this issue of PNAS, Reynaert et al. (5) lend a hand in the unveiling of S-nitrosylation as it operates in cellular context by elucidating a role in regulating NF-κB. NF-κB denotes a ubiquitous family of transcription factors that transduce a wide range of noxious or inflammatory stimuli into the coordinated activation of multiple genes, including those coding for cytokines, cytokine receptors, adhesion molecules, and antiapoptotic proteins (6). NF-κB thus serves as a critical element in immune and inflammatory responses and in cell survival and proliferation, with central roles in host defense and in acute and chronic disorders of immune function. NF-κB can upregulate the expression of all major NO synthases (nNOS, iNOS, and eNOS). It is well established that NF-κB is complexed with and sequestered in the cytoplasm by inhibitory IκB (inhibitor of NF-κB) proteins and that many activating stimuli induce phosphorylation of IκB by the IκB-kinase complex (IKKα, IKKβ, and IKKγ), initiate IκB ubiquitinylation and degradation by means of the 26S proteasome, and allow translocation of NF-κB to the nucleus (6). The molecular cascades that run through NF-κB present multiple loci at which oxidative/nitrosative modification could potentially modulate signal transduction, but the role of NF-κB and its attendant proteins in physiological redox responsivity …