Fig. 2

Scheme of TNFR1-mediated NF- κB activation. Following the ligation of cytokine TNF α to its receptor TNFR1, the receptor oligomerizes at the membrane and undergoes a conformational change to expose its death domain to the cytosol. Adaptor protein TRADD binds to the death domain and recruits RIP1. TRAF2 binds and recruits in turn E3 ligases, cIAP1 and cIAP2, which catalyze the formation of polyubiquitin chains on RIP1. These polyubiquitin chains serve as a scaffold for the kinases, TAK1 and IKK, to get recruited to the receptor signaling complex (RSC). Organized in proximity, the kinases cross-phosphorylate, and subsequently IKK phosphorylates the inhibitor of NF- κB, I κB, to target it for proteasomal degradation. The transcription factor, NF- κB, is released and translocates into the nucleus due to the exposed nuclear localization signal (NLS). In the nucleus, the transcription factor initiates the gene expression of several target genes. Among them are proteins that regulate NF- κB activation and terminate signal transduction. I κB gets restored in the cytosol, binds the transcription factor in the nucleus to form the inhibitory complex and shuttles it back into the cytosol. A20 is a deubiquitinase, which hydrolyzes the ubiquitin chains and targets RIP1 with K48-linked ubiquitin molecules for proteasomal degradation. The degradation of ubiquitin chains and RIP1 results in the dissociation of the RSC and eventually terminates signal transduction