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

  • YoungSik Cho
  • Sreerupa Challa
  • Francis Ka-Ming Chan
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 691)

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.

Keywords

RIP3 Complex Vaccinia Virus Infection Riboflavin Kinase Control Reactive Oxygen Species Control Reactive Oxygen Species Production 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

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.

References

  1. 1.
    Galluzzi L, Kepp O, Kroemer G(2009) RIP kinases initiate programmed necrosis. J Mol Cell Biol 2009 1(1):8–10Google Scholar
  2. 2.
    Kono H, Rock KL (2008) How dying cells alert the immune system to danger. Nat Rev Immunol 8(4):279–289CrossRefPubMedGoogle Scholar
  3. 3.
    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):489–495CrossRefPubMedGoogle Scholar
  4. 4.
    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):51613–51621CrossRefPubMedGoogle Scholar
  5. 5.
    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):10822–10828CrossRefPubMedGoogle Scholar
  6. 6.
    Cho YS et al (2009) Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 137(6):1112–11123CrossRefPubMedGoogle Scholar
  7. 7.
    Micheau O, Tschopp J (2003) Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 114(2):181–190CrossRefPubMedGoogle Scholar
  8. 8.
    Degterev A et al (2008) Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol 4(5):313–321CrossRefPubMedGoogle Scholar
  9. 9.
    Vanlangenakker N et al (2008) Molecular mechanisms and pathophysiology of necrotic cell death. Curr Mol Med 8(3):207–220CrossRefPubMedGoogle Scholar
  10. 10.
    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):675–687CrossRefPubMedGoogle Scholar
  11. 11.
    Yazdanpanah B et al (2009) Riboflavin kinase couples TNF receptor 1 to NADPH oxidase. Nature 460(7259):1159–1163CrossRefPubMedGoogle Scholar
  12. 12.
    Zhang J et al (1998) Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mort1. Nature 392(6673):296–300CrossRefPubMedGoogle Scholar
  13. 13.
    Chun HJ et al (2002) Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. Nature 419(6905):395–399CrossRefPubMedGoogle Scholar
  14. 14.
    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):3033–3044PubMedGoogle Scholar
  15. 15.
    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):16677–16682CrossRefPubMedGoogle Scholar
  16. 16.
    Ch’en IL et al (2008) Antigen-mediated T cell expansion regulated by parallel pathways of death. Proc Natl Acad Sci USA 105(45):17463–17468CrossRefPubMedGoogle Scholar
  17. 17.
    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):7470–7477CrossRefPubMedGoogle Scholar
  18. 18.
    He S et al (2009) Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell 137(6):1100–1111CrossRefPubMedGoogle Scholar
  19. 19.
    Zhang DW et al (2009) RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 325(5938):332–336CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • YoungSik Cho
    • 1
    • 2
    • 3
  • Sreerupa Challa
    • 1
  • Francis Ka-Ming Chan
    • 1
  1. 1.Department of PathologyUniversity of Massachusetts Medical SchoolWorcesterUSA
  2. 2.Immunology and Virology ProgramUniversity of Massachusetts Medical SchoolWorcesterUSA
  3. 3.Center for Metabolic Syndrome Therapeutics, Bio-Organic Science DivisionKorea Research Institute of Chemical TechnologyDaejeonKorea

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