Necroptosis as an alternative form of programmed cell death

Abstract

The family of death receptors plays a critical role in regulating cell number and eliminating harmful or virally infected cells. Agonistic stimulation of death receptors is known to lead two alternative cell fates by either activating NF-kappaB to promote cell survival or inducing apoptosis to lead to cell death; and now a third pathway, termed necroptosis or programmed necrosis has been identified. Interestingly, a death-domain containing kinase, RIP1, is involved in mediating all three pathways, with its kinase activity specifically involved in regulating necroptosis. The availability of necrostatin-1, a specific inhibitor of RIP1 kinase, made it possible to dissect the distinct functional domains of RIP1. Recent genome-wide siRNA screens have identified multiple players of necroptosis that may interact with and/or regulate RIP1 kinase and mediate the signaling pathway and execution of necroptosis. Necroptosis and necrostatins provide an exciting new opportunity for developing new treatments for multiple human diseases involving necrosis and inflammation.

Figure 1

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.