Fig. 1.

Overview of the NF-κB activation pathways and the impact of S-glutathionylation. A) Schematic representation of activation of classical (top) and alternative (bottom) NF-κB activation pathways, and outcomes. The classical pathway is activated by diverse ligands, such as LPS, Tumor Necrosis Factor-alpha (TNFα), Interleukin 1-beta (IL-1β), among many others, which results in the activation of Inhibitory kappa B kinase beta (IKKβ) which in turn mediates degradation of IκBα, resulting in the nuclear translocation and activation of RelA/p50 NF-kB subunits. The alternative NF-κB pathway is activated by distinct subsets of ligands, such as B cell Activating Factor (BAFF), CD40 ligand (CD40L) etc. which result in NF-κB Inducing Kinase (NIK) dependent activation of I kappa B kinase alpha (IKKα) which phosphorylates p100, and resultant proteolytic processing to p52. RelB/p52 dimeric complexes then are translocated to the nucleus, to activate transcription of unique sets of genes. Note that this schematic is an oversimplification, as additional regulatory post-translational modifications, and chromatin remodeling events occur to enable transcriptional activation of genes. Cross talk between classical and alternative NF-κB pathways also occurs, and is not illustrated here. B) Impact of H₂O₂ of IKKβ and NF-κB signaling. Stimulation of cells with LPS or TNFα leads to activation of IKKβ, and downstream NF-κB signaling. In the presence of H₂O₂ (100–200 μM) or following overexpression of NOX1, IKKβ is inhibited via S-glutathionylation (-SSG) of Cys179. Overexpression of glutaredoxin-1 (Grx1) reverses S-glutathionylation of IKKβ (-SH), and permits NF-κB signaling in the presence of H₂O₂. This schematic is a summary of previously published data [10].