Date: 22 Oct 2010

A RNA Interference Screen Identifies RIP3 as an Essential Inducer of TNF-Induced Programmed Necrosis

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Recent evidence indicates that TNF-like death cytokines can induce apoptotic and non-apoptotic forms of cell death. We have coined the term “programmed necrosis” to describe caspase-independent cell death induced by TNF-like cytokines. Besides an obligate requirement for the protein serine/threonine kinase RIP1 and the production of reactive oxygen species (ROS), relatively little is known about the molecular mechanisms that control TNF-induced programmed necrosis. In order to further illuminate the molecular pathway that governs programmed necrosis, we performed a targeted RNA interference (RNAi) screen. Our screen identified RIP3, a RIP1 family member, as a specific mediator for programmed necrosis, but not apoptosis. Biochemical analyses show that assembly of the pro-necrotic RIP1–RIP3 complex critically regulates induction of programmed necrosis. The physiological relevance of RIP3-dependent programmed necrosis is demonstrated by the failure of RIP3-deficient mice to control vaccinia virus infections.