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.
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