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. Author manuscript; available in PMC: 2016 Dec 1.
Published in final edited form as: Curr Pathobiol Rep. 2015 Sep 30;3(4):253–261. doi: 10.1007/s40139-015-0093-z

Figure 1. Activation of TNF signaling.

Figure 1

TNFα binding to TNFR1 causes Complex I formation by recruitment of TRADD, RIP1, TRAF2/5, cIAP1/2, and LUBAC. cIAP1/2 promotes K63-linked polyubiquitination of RIP1, whereas A20 and CYLD deubiquitinates RIP1. In the Complex I, K63-linked polyubiquitination of RIP1 mediates TAK1-TAB1-TAB2/3 complex recruitment. TAK1 is responsible for the phosphorylation and activation of IKK complex, resulting in IκBα degradation and NF-κB-mediated gene transcription. Inactivation of cIAP1 or deubiquitination of RIP1 by CYLD facilitates Complex I transition to Complex II. Complex IIa consists of TRADD, RIP1, FADD and caspase-8, which induces apoptosis. Inhibition of caspase-8 or FADD causes the formation of Complex IIb, ultimately leading to necroptosis.