Recruitment of NEMO to ubiquitinated RIP1 prevents programmed necrosis.

A model that represents the early pro-survival effect of RIP1 ubiquitination is shown. In the first few minutes after ligation of TNFR1, lysine 377 of RIP1 is conjugated to non-degradative ubiquitin chains by the concerted action of the E3 ligases cIAP1, cIAP2 and TRAF2. The bi-partite ubiquitin binding domain of NEMO docks with ubiquitinated RIP1 and this stimulus-specific interaction restrains the kinase domain of RIP1 from instigating cell death by programmed necrosis. In the absence of NEMO, the ubiquitin chains on RIP1 are likely removed by the action of the CYLD deubiquitinase and RIP1 becomes a pro-death signaling molecule that can trigger programmed necrosis when caspase activity is blocked. The pro-survival complex of TNFR1 (I) is the default scenario but a pro-death complex (II) is predicted to arise physiologically when the ubiquitination of RIP1 is prevented by ligation of TNFR2, which triggers degradation of TRAF2, cIAP1 and cIAP2.