Abstract
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.
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References
Galluzzi L, Kepp O, Kroemer G(2009) RIP kinases initiate programmed necrosis. J Mol Cell Biol 2009 1(1):8–10
Kono H, Rock KL (2008) How dying cells alert the immune system to danger. Nat Rev Immunol 8(4):279–289
Holler N et al (2000) Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol 1(6):489–495
Chan FK et al (2003) A role for tumor necrosis factor receptor-2 and receptor-interacting protein in programmed necrosis and antiviral responses. J Biol Chem 278(51):51613–51621
Lin Y et al (2004) Tumor necrosis factor-induced nonapoptotic cell death requires receptor-interacting protein-mediated cellular reactive oxygen species accumulation. J Biol Chem 279(11):10822–10828
Cho YS et al (2009) Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 137(6):1112–11123
Micheau O, Tschopp J (2003) Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 114(2):181–190
Degterev A et al (2008) Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol 4(5):313–321
Vanlangenakker N et al (2008) Molecular mechanisms and pathophysiology of necrotic cell death. Curr Mol Med 8(3):207–220
Kim YS et al (2007) TNF-induced activation of the Nox1 NADPH oxidase and its role in the induction of necrotic cell death. Mol Cell 26(5):675–687
Yazdanpanah B et al (2009) Riboflavin kinase couples TNF receptor 1 to NADPH oxidase. Nature 460(7259):1159–1163
Zhang J et al (1998) Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mort1. Nature 392(6673):296–300
Chun HJ et al (2002) Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. Nature 419(6905):395–399
Zhang Y et al (2005) Conditional Fas-associated death domain protein (FADD): GFP knockout mice reveal FADD is dispensable in thymic development but essential in peripheral T cell homeostasis. J Immunol 175(5):3033–3044
Bell BD et al (2008) FADD and caspase-8 control the outcome of autophagic signaling in proliferating T cells. Proc Natl Acad Sci USA 105(43):16677–16682
Ch’en IL et al (2008) Antigen-mediated T cell expansion regulated by parallel pathways of death. Proc Natl Acad Sci USA 105(45):17463–17468
Li M, Beg AA (2000) Induction of necrotic-like cell death by tumor necrosis factor alpha and caspase inhibitors: novel mechanism for killing virus-infected cells. J Virol 74(16):7470–7477
He S et al (2009) Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell 137(6):1100–1111
Zhang DW et al (2009) RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 325(5938):332–336
Acknowledgment
This work was supported by NIH grant AI065877. F.K.C. was a recipient of investigator awards from the Smith Family Foundation and the Cancer Research Institute.
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Cho, Y., Challa, S., Chan, F.KM. (2011). A RNA Interference Screen Identifies RIP3 as an Essential Inducer of TNF-Induced Programmed Necrosis. In: Wallach, D., Kovalenko, A., Feldmann, M. (eds) Advances in TNF Family Research. Advances in Experimental Medicine and Biology, vol 691. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-6612-4_62
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DOI: https://doi.org/10.1007/978-1-4419-6612-4_62
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