Figure 8. Activation of RIP1-mediated necroptosis.

TNF-α binding to TNFR1 can activate NF-κB activation, apoptosis, or necroptosis. Phosphorylation of TNFR1 favours TRADD recruitment that in turn leads to RIP1 ubiquitination (complex I), and the subsequent activation of the NF-κB pathway via NEMO. Inhibition of PKC delta leads to the deubiquitination of RIP1 and the formation of either complex IIa with FADD and caspase-8, or, if RIP1 is phosphorylated, the formation of a necrosome with phosphorylated RIP3 (complex IIb), leading to necroptosis. A dimer between HOX and PBX proteins represses the necroptosis pathway, possibly through inhibition of RIP kinase. HOX/PBX dimers also repress p21 expression, which might in turn block apoptosis (dotted line). Abbreviations: PKC, protein kinase C; NEMO, NF-kappa-B essential modulator; RIP1, Receptor-interacting protein 1; cIAP2, Cellular inhibitor of apoptosis-1; TRAF, TNF receptor associated factors; FADD, Fas-associated protein with death domain; TRADD, Tumor necrosis factor receptor type 1-associated death domain protein.