Signaling complexes induced by TNFA to mediate NFKB activation, apoptosis and necroptosis

The signaling complexes induced by TNFα to mediate NF-κB activation, apoptosis and necroptosis. Stimulation of TNFR1 by TNFα leads to the formation of an intracellular complex at the cytoplasmic membrane (complex I) that includes TRADD, TRAF2, RIP1 and cIAP1. Ubiquitination of RIP1 at K377 by cIAP1 leads to the recruitment of NEMO, a regulatory subunit of IKK complex that in turn activates NF-κB pathway. RIP1 is also involved in the formation of complex IIa including FADD and caspase-8 to activate a caspase cascade to mediate apoptosis. Under apoptosis deficient conditions or when cells are infected by certain virus, RIP1 interacts with RIP3 to form complex IIb which is involved in mediating necroptosis. The formation complex IIb requires the kinase activity of RIP1 that is inhibited by Nec-1.

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Necroptosis as an alternative form of programmed cell death. () Dana E. Christofferson, et al. Curr Opin Cell Biol. ;22(2):263-268. Figure: F1. Homo sapiens

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