1932

Abstract

Cell proliferation and cell death are integral elements in maintaining homeostatic balance in metazoans. Disease pathologies ensue when these processes are disturbed. A plethora of evidence indicates that malfunction of cell death can lead to inflammation, autoimmunity, or immunodeficiency. Programmed necrosis or necroptosis is a form of nonapoptotic cell death driven by the receptor interacting protein kinase 3 (RIPK3) and its substrate, mixed lineage kinase domain-like (MLKL). RIPK3 partners with its upstream adaptors RIPK1, TRIF, or DAI to signal for necroptosis in response to death receptor or Toll-like receptor stimulation, pathogen infection, or sterile cell injury. Necroptosis promotes inflammation through leakage of cellular contents from damaged plasma membranes. Intriguingly, many of the signal adaptors of necroptosis have dual functions in innate immune signaling. This unique signature illustrates the cooperative nature of necroptosis and innate inflammatory signaling pathways in managing cell and organismal stresses from pathogen infection and sterile tissue injury.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-immunol-032414-112248
2015-03-21
2024-03-29
Loading full text...

Full text loading...

/deliver/fulltext/immunol/33/1/annurev-immunol-032414-112248.html?itemId=/content/journals/10.1146/annurev-immunol-032414-112248&mimeType=html&fmt=ahah

Literature Cited

  1. Segawa K, Kurata S, Yanagihashi Y, Brummelkamp TR, Matsuda F, Nagata S. 1.  2014. Caspase-mediated cleavage of phospholipid flippase for apoptotic phosphatidylserine exposure. Science 344:1164–68 [Google Scholar]
  2. Suzuki J, Imanishi E, Nagata S. 2.  2013. Exposure of phosphatidylserine by Xk-related protein family members during apoptosis. J. Biol. Chem. 289:30257–67 [Google Scholar]
  3. Hochreiter-Hufford A, Ravichandran KS. 3.  2013. Clearing the dead: apoptotic cell sensing, recognition, engulfment, and digestion. Cold Spring Harb. Perspect. Biol. 5:a008748 [Google Scholar]
  4. Kono H, Rock KL. 4.  2008. How dying cells alert the immune system to danger. Nat. Rev. Immunol. 8:279–89 [Google Scholar]
  5. Sawai H, Domae N. 5.  2011. Discrimination between primary necrosis and apoptosis by necrostatin-1 in Annexin V-positive/propidium iodide-negative cells. Biochem. Biophys. Res. Commun. 411:569–73 [Google Scholar]
  6. Yamasaki S, Ishikawa E, Sakuma M, Hara H, Ogata K, Saito T. 6.  2008. Mincle is an ITAM-coupled activating receptor that senses damaged cells. Nat. Immunol. 9:1179–88 [Google Scholar]
  7. Sancho D, Joffre OP, Keller AM, Rogers NC, Martinez D. 7.  et al. 2009. Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Nature 458:899–903 [Google Scholar]
  8. Günther C, Martini E, Wittkopf N, Amann K, Weigmann B. 8.  et al. 2011. Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis. Nature 477:335–39 [Google Scholar]
  9. Moriwaki K, Chan FKM. 9.  2013. RIP3: a molecular switch for necrosis and inflammation. Genes Dev. 27:1640–49 [Google Scholar]
  10. Sosna J, Voigt S, Mathieu S, Lange A, Thon L. 10.  et al. 2013. TNF-induced necroptosis and PARP-1-mediated necrosis represent distinct routes to programmed necrotic cell death. Cell. Mol. Life Sci. 71:331–48 [Google Scholar]
  11. Fu D, Jordan JJ, Samson LD. 11.  2013. Human ALKBH7 is required for alkylation and oxidation-induced programmed necrosis. Genes Dev. 27:1089–100 [Google Scholar]
  12. Thapa RJ, Nogusa S, Chen P, Maki JL, Lerro A. 12.  et al. 2013. Interferon-induced RIP1/RIP3-mediated necrosis requires PKR and is licensed by FADD and caspases. PNAS 110:E3109–18 [Google Scholar]
  13. Chan FKM, Chun HJ, Zheng L, Siegel RM, Bui KL, Lenardo MJ. 13.  2000. A domain in TNF receptors that mediates ligand-independent receptor assembly and signaling. Science 288:2351–54 [Google Scholar]
  14. Micheau O, Tschopp J. 14.  2003. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 114:181–90 [Google Scholar]
  15. Rieser E, Cordier SM, Walczak H. 15.  2013. Linear ubiquitination: a newly discovered regulator of cell signalling. Trends Biochem. Sci. 38:94–102 [Google Scholar]
  16. Papa S, Zazzeroni F, Bubici C, Jayawardena S, Alvarez K. 16.  et al. 2004. Gadd45β mediates the NF-κB suppression of JNK signalling by targeting MKK7/JNKK2. Nat. Cell Biol. 6:146–53 [Google Scholar]
  17. Kreuz S, Siegmund D, Scheurich P, Wajant H. 17.  2001. NF-κB inducers upregulate cFLIP, a cycloheximide-sensitive inhibitor of death receptor signaling. Mol. Cell. Biol. 21:3964–73 [Google Scholar]
  18. Moulin M, Anderton H, Voss AK, Thomas T, Wong WW. 18.  et al. 2012. IAPs limit activation of RIP kinases by TNF receptor 1 during development. EMBO J. 31:1679–91 [Google Scholar]
  19. Csomos RA, Brady GF, Duckett CS. 19.  2009. Enhanced cytoprotective effects of the inhibitor of apoptosis protein cellular IAP1 through stabilization with TRAF2. J. Biol. Chem. 284:20531–39 [Google Scholar]
  20. Yeh WC, Shahinian A, Speiser D, Kraunus J, Billia F. 20.  et al. 1997. Early lethality, functional NF-κB activation, and increased sensitivity to TNF-induced cell death in TRAF2-deficient mice. Immunity 7:715–25 [Google Scholar]
  21. Ikeda F, Deribe YL, Skånland SS, Stieglitz B, Grabbe C. 21.  et al. 2011. SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis. Nature 471:637–41 [Google Scholar]
  22. Tokunaga F, Nakagawa T, Nakahara M, Saeki Y, Taniguchi M. 22.  et al. 2011. SHARPIN is a component of the NF-κB-activating linear ubiquitin chain assembly complex. Nature 471:633–36 [Google Scholar]
  23. Gerlach B, Cordier SM, Schmukle AC, Emmerich CH, Rieser E. 23.  et al. 2011. Linear ubiquitination prevents inflammation and regulates immune signalling. Nature 471:591–96 [Google Scholar]
  24. Harper N, Hughes M, MacFarlane M, Cohen GM. 24.  2003. Fas-associated death domain protein and caspase-8 are not recruited to the tumor necrosis factor receptor 1 signaling complex during tumor necrosis factor-induced apoptosis. J. Biol. Chem. 278:25534–41 [Google Scholar]
  25. Schneider-Brachert W, Tchikov V, Neumeyer J, Jakob M, Winoto-Morbach S. 25.  et al. 2004. Compartmentalization of TNF receptor 1 signaling: internalized TNF receptosomes as death signaling vesicles. Immunity 21:415–28 [Google Scholar]
  26. Lin Y, Devin A, Rodriguez Y, Liu ZG. 26.  1999. Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis. Genes Dev. 13:2514–26 [Google Scholar]
  27. Feng S, Yang Y, Mei Y, Ma L, Zhu DE. 27.  et al. 2007. Cleavage of RIP3 inactivates its caspase-independent apoptosis pathway by removal of kinase domain. Cell. Signal. 19:2056–67 [Google Scholar]
  28. Oberst A, Dillon CP, Weinlich R, McCormick LL, Fitzgerald P. 28.  et al. 2011. Catalytic activity of the caspase-8-FLIPL complex inhibits RIPK3-dependent necrosis. Nature 471:363–67 [Google Scholar]
  29. Pop C, Oberst A, Drag M, Van Raam BJ, Riedl SJ. 29.  et al. 2011. FLIPL induces caspase-8 activity in the absence of interdomain caspase-8 cleavage and alters substrate specificity. Biochem. J. 433:447–57 [Google Scholar]
  30. O'Donnell MA, Perez-Jimenez E, Oberst A, Ng A, Massoumi R. 30.  et al. 2011. Caspase-8 inhibits programmed necrosis by processing CYLD. Nat. Cell Biol. 13:1437–42 [Google Scholar]
  31. Tenev T, Bianchi K, Darding M, Broemer M, Langlais C. 31.  et al. 2011. The Ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPs. Mol. Cell 43:432–48 [Google Scholar]
  32. Feoktistova M, Geserick P, Kellert B, Dimitrova DP, Langlais C. 32.  et al. 2011. cIAPs block Ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms. Mol. Cell 43:449–63 [Google Scholar]
  33. Li J, McQuade T, Siemer AB, Napetschnig J, Moriwaki K. 33.  et al. 2012. The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. Cell 150:339–50 [Google Scholar]
  34. Sun L, Wang H, Wang Z, He S, Chen S. 34.  et al. 2012. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell 148:213–27 [Google Scholar]
  35. Zhao J, Jitkaew S, Cai Z, Choksi S, Li Q. 35.  et al. 2012. Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis. PNAS 109:5322–27 [Google Scholar]
  36. Cai Z, Jitkaew S, Zhao J, Chiang HC, Choksi S. 36.  et al. 2014. Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis. Nat. Cell Biol. 16:55–65 [Google Scholar]
  37. Chen X, Li W, Ren J, Huang D, He WT. 37.  et al. 2014. Translocation of mixed lineage kinase domain-like protein to plasma membrane leads to necrotic cell death. Cell Res. 24:105–21 [Google Scholar]
  38. Wang H, Sun L, Su L, Rizo J, Liu L. 38.  et al. 2014. Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol. Cell 54:133–46 [Google Scholar]
  39. Dondelinger Y, Declercq W, Montessuit S, Roelandt R, Goncalves A. 39.  et al. 2014. MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates. Cell Rep. 7:971–81 [Google Scholar]
  40. Wang Z, Jiang H, Chen S, Du F, Wang X. 40.  2012. The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways. Cell 148:228–43 [Google Scholar]
  41. Murphy JM, Czabotar PE, Hildebrand JM, Lucet IS, Zhang JG. 41.  et al. 2013. The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism. Immunity 39:443–53 [Google Scholar]
  42. Remijsen Q, Goossens V, Grootjans S, Van den Haute C, Vanlangenakker N. 42.  et al. 2014. Depletion of RIPK3 or MLKL blocks TNF-driven necroptosis and switches towards a delayed RIPK1 kinase-dependent apoptosis. Cell Death Dis. 5:e1004 [Google Scholar]
  43. Tait SW, Oberst A, Quarato G, Milasta S, Haller M. 43.  et al. 2013. Widespread mitochondrial depletion via mitophagy does not compromise necroptosis. Cell Rep. 5:878–85 [Google Scholar]
  44. Kaiser WJ, Upton JW, Long AB, Livingston-Rosanoff D, Daley-Bauer LP. 44.  et al. 2011. RIP3 mediates the embryonic lethality of caspase-8-deficient mice. Nature 471:368–72 [Google Scholar]
  45. Zhang H, Zhou X, McQuade T, Li J, Chan FKM, Zhang J. 45.  2011. Functional complementation between FADD and RIP1 in embryos and lymphocytes. Nature 471:373–76 [Google Scholar]
  46. Welz PS, Wullaert A, Vlantis K, Kondylis V, Fernandez-Majada V. 46.  et al. 2011. FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation. Nature 477:330–34 [Google Scholar]
  47. Bonnet MC, Preukschat D, Welz PS, van Loo G, Ermolaeva MA. 47.  et al. 2011. The adaptor protein FADD protects epidermal keratinocytes from necroptosis in vivo and prevents skin inflammation. Immunity 35:572–82 [Google Scholar]
  48. Ch'en IL, Tsau JS, Molkentin JD, Komatsu M, Hedrick SM. 48.  2011. Mechanisms of necroptosis in T cells. J. Exp. Med. 208:633–41 [Google Scholar]
  49. Lu JV, Weist BM, van Raam BJ, Marro BS, Nguyen LV. 49.  et al. 2011. Complementary roles of Fas-associated death domain (FADD) and receptor interacting protein kinase-3 (RIPK3) in T-cell homeostasis and antiviral immunity. PNAS 108:15312–17 [Google Scholar]
  50. Holler N, Zaru R, Micheau O, Thome M, Attinger A. 50.  et al. 2000. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat. Immunol. 1:489–95 [Google Scholar]
  51. Dillon CP, Oberst A, Weinlich R, Janke LJ, Kang TB. 51.  et al. 2012. Survival function of the FADD-CASPASE-8-cFLIPL complex. Cell Rep. 1:401–7 [Google Scholar]
  52. Zhang SQ, Kovalenko A, Cantarella G, Wallach D. 52.  2000. Recruitment of the IKK signalosome to the p55 TNF receptor: RIP and A20 bind to NEMO (IKKγ) upon receptor stimulation. Immunity 12:301–11 [Google Scholar]
  53. Ea CK, Deng L, Xia ZP, Pineda G, Chen ZJ. 53.  2006. Activation of IKK by TNFα requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO. Mol. Cell 22:245–57 [Google Scholar]
  54. Wu CJ, Conze DB, Li T, Srinivasula SM, Ashwell JD. 54.  2006. Sensing of Lys 63-linked polyubiquitination by NEMO is a key event in NF-κB activation. Nat. Cell Biol. 8:398–406 [Google Scholar]
  55. O'Donnell MA, Hase H, Legarda D, Ting AT. 55.  2012. NEMO inhibits programmed necrosis in an NFκB-independent manner by restraining RIP1. PLOS ONE 7e41238
  56. O'Donnell MA, Legarda-Addison D, Skountzos P, Yeh WC, Ting AT. 56.  2007. Ubiquitination of RIP1 regulates an NF-κB-independent cell-death switch in TNF signaling. Curr. Biol. 17:418–24 [Google Scholar]
  57. Varfolomeev E, Blankenship JW, Wayson SM, Fedorova AV, Kayagaki N. 57.  et al. 2007. IAP antagonists induce autoubiquitination of c-IAPs, NF-κB activation, and TNFα-dependent apoptosis. Cell 131:669–81 [Google Scholar]
  58. Vince JE, Wong WW, Khan N, Feltham R, Chau D. 58.  et al. 2007. IAP antagonists target cIAP1 to induce TNFα-dependent apoptosis. Cell 131:682–93 [Google Scholar]
  59. Bertrand MJ, Milutinovic S, Dickson KM, Ho WC, Boudreault A. 59.  et al. 2008. cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. Mol. Cell 30:689–700 [Google Scholar]
  60. Dueber EC, Schoeffler AJ, Lingel A, Elliott JM, Fedorova AV. 60.  et al. 2011. Antagonists induce a conformational change in cIAP1 that promotes autoubiquitination. Science 334:376–80 [Google Scholar]
  61. Petersen SL, Peyton M, Minna JD, Wang X. 61.  2010. Overcoming cancer cell resistance to Smac mimetic induced apoptosis by modulating cIAP-2 expression. PNAS 107:11936–41 [Google Scholar]
  62. Chromik J, Safferthal C, Serve H, Fulda S. 62.  2014. Smac mimetic primes apoptosis-resistant acute myeloid leukaemia cells for cytarabine-induced cell death by triggering necroptosis. Cancer Lett. 344:101–9 [Google Scholar]
  63. Kim EY, Teh HS. 63.  2004. Critical role of TNF receptor type-2 (p75) as a costimulator for IL-2 induction and T cell survival: a functional link to CD28. J. Immunol. 173:4500–9 [Google Scholar]
  64. Chan FKM, Lenardo MJ. 64.  2000. A crucial role for p80 TNF-R2 in amplifying p60 TNF-R1 apoptosis signals in T lymphocytes. Eur. J. Immunol. 30:652–60 [Google Scholar]
  65. Chan FKM, Shisler J, Bixby JG, Felices M, Zheng L. 65.  et al. 2003. A role for tumor necrosis factor receptor-2 and receptor-interacting protein in programmed necrosis and antiviral responses. J. Biol. Chem. 278:51613–21 [Google Scholar]
  66. Li X, Yang Y, Ashwell JD. 66.  2002. TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2. Nature 416:345–47 [Google Scholar]
  67. Fotin-Mleczek M, Henkler F, Samel D, Reichwein M, Hausser A. 67.  et al. 2002. Apoptotic crosstalk of TNF receptors: TNF-R2-induces depletion of TRAF2 and IAP proteins and accelerates TNF-R1-dependent activation of caspase-8. J. Cell Sci. 115:2757–70 [Google Scholar]
  68. Wong WW, Vince JE, Lalaoui N, Lawlor KE, Chau D. 68.  et al. 2014. cIAPs and XIAP regulate myelopoiesis through cytokine production in an RIPK1- and RIPK3-dependent manner. Blood 123:2562–72 [Google Scholar]
  69. Vanlangenakker N, Vanden Berghe T, Bogaert P, Laukens B, Zobel K. 69.  et al. 2011. cIAP1 and TAK1 protect cells from TNF-induced necrosis by preventing RIP1/RIP3-dependent reactive oxygen species production. Cell Death Differ. 18:656–65 [Google Scholar]
  70. Tokunaga F, Sakata S, Saeki Y, Satomi Y, Kirisako T. 70.  et al. 2009. Involvement of linear polyubiquitylation of NEMO in NF-κB activation. Nat. Cell Biol. 11:123–32 [Google Scholar]
  71. Berger S, Kasparcova V, Hoffman S, Swift B, Dare L. 71.  et al. 2014. Cutting edge: RIP1 kinase activity is dispensable for normal development but is a key regulator of inflammation in SHARPIN-deficient mice. J. Immunol. 192:5476–80 [Google Scholar]
  72. Newton K, Dugger D, Wickliffe KE, Kapoor N, de Almagro C. 72.  et al. 2014. Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosis. Science 343:1357–60 [Google Scholar]
  73. Wang L, Du F, Wang X. 73.  2008. TNF-α induces two distinct caspase-8 activation pathways. Cell 133:693–703 [Google Scholar]
  74. Boisson B, Laplantine E, Prando C, Giliani S, Israelsson E. 74.  et al. 2012. Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency. Nat. Immunol. 13:1178–86 [Google Scholar]
  75. Nilsson J, Schoser B, Laforet P, Kalev O, Lindberg C. 75.  et al. 2013. Polyglucosan body myopathy caused by defective ubiquitin ligase RBCK1. Ann. Neurol. 74:914–19 [Google Scholar]
  76. Makris C, Godfrey VL, Krähn-Senftleben G, Takahashi T, Roberts JL. 76.  et al. 2000. Female mice heterozygous for IKKγ/NEMO deficiencies develop a dermatopathy similar to the human X-linked disorder incontinentia pigmenti. Mol. Cell 5:969–79 [Google Scholar]
  77. Rudolph D, Yeh WC, Wakeham A, Rudolph B, Nallainathan D. 77.  et al. 2000. Severe liver degeneration and lack of NF-κB activation in NEMO/IKKγ-deficient mice. Genes Dev. 14:854–62 [Google Scholar]
  78. Schmidt-Supprian M, Bloch W, Courtois G, Addicks K, Israël A. 78.  et al. 2000. NEMO/IKKγ-deficient mice model incontinentia pigmenti. Mol. Cell 5:981–92 [Google Scholar]
  79. Döffinger R, Smahi A, Bessia C, Geissmann F, Feinberg J. 79.  et al. 2001. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-κB signaling. Nat. Genet. 27:277–85 [Google Scholar]
  80. Hitomi J, Christofferson DE, Ng A, Yao J, Degterev A. 80.  et al. 2008. Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell 135:1311–23 [Google Scholar]
  81. Moquin DM, McQuade T, Chan FKM. 81.  2013. CYLD deubiquitinates RIP1 in the TNFα-induced necrosome to facilitate kinase activation and programmed necrosis. PLOS ONE 8:e76841 [Google Scholar]
  82. Kelliher MA, Grimm S, Ishida Y, Kuo F, Stanger BZ, Leder P. 82.  1998. The death domain kinase RIP mediates the TNF-induced NF-κB signal. Immunity 8:297–303 [Google Scholar]
  83. Wong WWL, Gentle IE, Nachbur U, Anderton H, Vaux DL, Silke J. 83.  2010. RIPK1 is not essential for TNFR1-induced activation of NF-κB. Cell Death Differ. 17:482–87 [Google Scholar]
  84. Dillon CP, Weinlich R, Rodriguez DA, Cripps JG, Quarato G. 84.  et al. 2014. RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3. Cell 157:1189–202 [Google Scholar]
  85. Rickard JA, O'Donnell JA, Evans JM, Lalaoui N, Poh AR. 85.  et al. 2014. RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis. Cell 157:1175–88 [Google Scholar]
  86. Kaiser WJ, Daley-Bauer LP, Thapa RJ, Mandal P, Berger SB. 86.  et al. 2014. RIP1 suppresses innate immune necrotic as well as apoptotic cell death during mammalian parturition. PNAS 111:7753–58 [Google Scholar]
  87. Takahashi N, Vereecke L, Bertrand MJM, Duprez L, Berger SB. 87.  et al. 2014. RIPK1 ensures intestinal homeostasis by protecting the epithelium against apoptosis. Nature 513:95–99 [Google Scholar]
  88. Dannappel M, Vlantis K, Kumari S, Polykratis A, Kim C. 88.  et al. 2014. RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis. Nature 513:90–94 [Google Scholar]
  89. Cho Y, Challa S, Chan FKM. 89.  2011. A RNA interference screen identifies RIP3 as an essential inducer of TNF-induced programmed necrosis. Adv. Exp. Med. Biol. 691:589–93 [Google Scholar]
  90. Cho YS, Challa S, Moquin D, Genga R, Ray TD. 90.  et al. 2009. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 137:1112–23 [Google Scholar]
  91. Kaiser WJ, Offermann MK. 91.  2005. Apoptosis induced by the Toll-like receptor adaptor TRIF is dependent on its receptor interacting protein homotypic interaction motif. J. Immunol. 174:4942–52 [Google Scholar]
  92. Meylan E, Burns K, Hofmann K, Blancheteau V, Martinon F. 92.  et al. 2004. RIP1 is an essential mediator of Toll-like receptor 3–induced NF-κB activation. Nat. Immunol. 5:503–7 [Google Scholar]
  93. Upton JW, Kaiser WJ, Mocarski ES. 93.  2010. Virus inhibition of RIP3-dependent necrosis. Cell Host Microbe 7:302–13 [Google Scholar]
  94. Upton JW, Kaiser WJ, Mocarski ES. 94.  2012. DAI/ZBP1/DLM-1 complexes with RIP3 to mediate virus-induced programmed necrosis that is targeted by murine cytomegalovirus vIRA. Cell Host Microbe 11:290–97 [Google Scholar]
  95. Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG. 95.  et al. 2008. The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nat. Immunol. 9:857–65 [Google Scholar]
  96. Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S. 96.  et al. 2013. NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature 493:674–78 [Google Scholar]
  97. Northington FJ, Chavez-Valdez R, Graham EM, Razdan S, Gauda EB, Martin LJ. 97.  2011. Necrostatin decreases oxidative damage, inflammation, and injury after neonatal HI. J. Cereb. Blood Flow Metab. 31:178–89 [Google Scholar]
  98. Chavez-Valdez R, Martin LJ, Flock DL, Northington FJ. 98.  2012. Necrostatin-1 attenuates mitochondrial dysfunction in neurons and astrocytes following neonatal hypoxia-ischemia. Neuroscience 219:192–203 [Google Scholar]
  99. He S, Liang Y, Shao F, Wang X. 99.  2011. Toll-like receptors activate programmed necrosis in macrophages through a receptor-interacting kinase-3–mediated pathway. PNAS 108:20054–59 [Google Scholar]
  100. Kaiser WJ, Sridharan H, Huang C, Mandal P, Upton JW. 100.  et al. 2013. Toll-like receptor 3-mediated necrosis via TRIF, RIP3, and MLKL. J. Biol. Chem. 288:31268–79 [Google Scholar]
  101. Rebsamen M, Meylan E, Curran J, Tschopp J. 101.  2008. The antiviral adaptor proteins Cardif and Trif are processed and inactivated by caspases. Cell Death Differ. 15:1804–11 [Google Scholar]
  102. Cho Y, McQuade T, Zhang HB, Zhang JK, Chan FKM. 102.  2011. RIP1-dependent and independent effects of necrostatin-1 in necrosis and T cell activation. PLOS ONE 6:e23209 [Google Scholar]
  103. Takahashi N, Duprez L, Grootjans S, Cauwels A, Nerinckx W. 103.  et al. 2012. Necrostatin-1 analogues: critical issues on the specificity, activity and in vivo use in experimental disease models. Cell Death Dis. 3:e437 [Google Scholar]
  104. McQuade T, Cho Y, Chan FKM. 104.  2013. Positive and negative phosphorylation regulates RIP1- and RIP3-induced programmed necrosis. Biochem. J. 456:409–15 [Google Scholar]
  105. Degterev A, Hitomi J, Germscheid M, Ch'en IL, Korkina O. 105.  et al. 2008. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat. Chem. Biol. 4:313–21 [Google Scholar]
  106. Wu XN, Yang ZH, Wang XK, Zhang Y, Wan H. 106.  et al. 2014. Distinct roles of RIP1–RIP3 hetero- and RIP3-RIP3 homo-interaction in mediating necroptosis. Cell Death Differ. 21:1709–20 [Google Scholar]
  107. Orozco S, Yatim N, Werner MR, Tran H, Gunja SY. 107.  et al. 2014. RIPK1 both positively and negatively regulates RIPK3 oligomerization and necroptosis. Cell Death Differ. 21:1511–21 [Google Scholar]
  108. Cook WD, Moujalled DM, Ralph TJ, Lock P, Young SN. 108.  et al. 2014. RIPK1- and RIPK3-induced cell death mode is determined by target availability. Cell Death Differ. 21:1600–12 [Google Scholar]
  109. Moujalled DM, Cook WD, Okamoto T, Murphy J, Lawlor KE. 109.  et al. 2013. TNF can activate RIPK3 and cause programmed necrosis in the absence of RIPK1. Cell Death Dis. 4:e465 [Google Scholar]
  110. Mandal P, Berger SB, Pillay S, Moriwaki K, Huang C. 110.  et al. 2014. RIP3 induces apoptosis independent of pronecrotic kinase activity. Mol. Cell 56481–95
  111. Zheng L, Fisher G, Miller RE, Peschon J, Lynch DH, Lenardo MJ. 111.  1995. Induction of apoptosis in mature T cells by tumour necrosis factor. Nature 377:348–51 [Google Scholar]
  112. Lenardo M, Chan FKM, Hornung F, McFarland H, Siegel R. 112.  et al. 1999. Mature T lymphocyte apoptosis—immune regulation in a dynamic and unpredictable antigenic environment. Annu. Rev. Immunol. 17:221–53 [Google Scholar]
  113. Petersen SL, Wang L, Yalcin-Chin A, Li L, Peyton M. 113.  et al. 2007. Autocrine TNFα signaling renders human cancer cells susceptible to Smac-mimetic-induced apoptosis. Cancer Cell 12:445–56 [Google Scholar]
  114. Vivarelli MS, McDonald D, Miller M, Cusson N, Kelliher M, Geha RS. 114.  2004. RIP links TLR4 to Akt and is essential for cell survival in response to LPS stimulation. J. Exp. Med. 200:399–404 [Google Scholar]
  115. Cusson-Hermance N, Khurana S, Lee TH, Fitzgerald KA, Kelliher MA. 115.  2005. Rip1 mediates the Trif-dependent Toll-like receptor 3- and 4-induced NF-κB activation but does not contribute to interferon regulatory factor 3 activation. J. Biol. Chem. 280:36560–66 [Google Scholar]
  116. Kasof GM, Prosser JC, Liu D, Lorenzi MV, Gomes BC. 116.  2000. The RIP-like kinase, RIP3, induces apoptosis and NF-κB nuclear translocation and localizes to mitochondria. FEBS Lett. 473:285–91 [Google Scholar]
  117. Yu PW, Huang BC, Shen M, Quast J, Chan E. 117.  et al. 1999. Identification of RIP3, a RIP-like kinase that activates apoptosis and NFκB. Curr. Biol. 9:539–42 [Google Scholar]
  118. Pazdernik NJ, Donner DB, Goebl MG, Harrington MA. 118.  1999. Mouse receptor interacting protein 3 does not contain a caspase-recruiting or a death domain but induces apoptosis and activates NF-κB. Mol. Cell. Biol. 19:6500–8 [Google Scholar]
  119. Sun X, Lee J, Navas T, Baldwin DT, Stewart TA, Dixit VM. 119.  1999. RIP3, a novel apoptosis-inducing kinase. J. Biol. Chem. 274:16871–75 [Google Scholar]
  120. Newton K, Sun X, Dixit VM. 120.  2004. Kinase RIP3 is dispensable for normal NF-κBs, signaling by the B-cell and T-cell receptors, tumor necrosis factor receptor 1, and Toll-like receptors 2 and 4. Mol. Cell. Biol. 24:1464–69 [Google Scholar]
  121. Moriwaki K, Balaji S, McQuade T, Malhotra N, Kang J, Chan FKM. 121.  2014. The necroptosis adaptor RIPK3 promotes injury-induced cytokine expression and tissue repair. Immunity 41:567–78 [Google Scholar]
  122. Lu A, Magupalli VG, Ruan J, Yin Q, Atianand MK. 122.  et al. 2014. Unified polymerization mechanism for the assembly of ASC-dependent inflammasomes. Cell 156:1193–206 [Google Scholar]
  123. Pop C, Salvesen GS. 123.  2009. Human caspases: activation, specificity, and regulation. J. Biol. Chem. 284:21777–81 [Google Scholar]
  124. Schleich K, Warnken U, Fricker N, Ozturk S, Richter P. 124.  et al. 2012. Stoichiometry of the CD95 death-inducing signaling complex: experimental and modeling evidence for a death effector domain chain model. Mol. Cell 47:306–19 [Google Scholar]
  125. Dickens LS, Boyd RS, Jukes-Jones R, Hughes MA, Robinson GL. 125.  et al. 2012. A death effector domain chain DISC model reveals a crucial role for caspase-8 chain assembly in mediating apoptotic cell death. Mol. Cell 47:291–305 [Google Scholar]
  126. Franklin BS, Bossaller L, De Nardo D, Ratter JM, Stutz A. 126.  et al. 2014. The adaptor ASC has extracellular and ‘prionoid’ activities that propagate inflammation. Nat. Immunol. 15:727–37 [Google Scholar]
  127. Baroja-Mazo A, Martin-Sánchez F, Gomez AI, Martinez CM, Amores-Iniesta J. 127.  et al. 2014. The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response. Nat. Immunol. 15:738–48 [Google Scholar]
  128. Cai X, Chen J, Xu H, Liu S, Jiang QX. 128.  et al. 2014. Prion-like polymerization underlies signal transduction in antiviral immune defense and inflammasome activation. Cell 156:1207–22 [Google Scholar]
  129. Peisley A, Wu B, Yao H, Walz T, Hur S. 129.  2013. RIG-I forms signaling-competent filaments in an ATP-dependent, ubiquitin-independent manner. Mol. Cell 51:573–83 [Google Scholar]
  130. Wu B, Peisley A, Richards C, Yao H, Zeng X. 130.  et al. 2013. Structural basis for dsRNA recognition, filament formation, and antiviral signal activation by MDA5. Cell 152:276–89 [Google Scholar]
  131. Maelfait J, Vercammen E, Janssens S, Schotte P, Haegman M. 131.  et al. 2008. Stimulation of Toll-like receptor 3 and 4 induces interleukin-1β maturation by caspase-8. J. Exp. Med. 205:1967–73 [Google Scholar]
  132. Gringhuis SI, Kaptein TM, Wevers BA, Theelen B, van der Vlist M. 132.  et al. 2012. Dectin-1 is an extracellular pathogen sensor for the induction and processing of IL-1β via a noncanonical caspase-8 inflammasome. Nat. Immunol. 13:246–54 [Google Scholar]
  133. Antonopoulos C, El Sanadi C, Kaiser WJ, Mocarski ES, Dubyak GR. 133.  2013. Proapoptotic chemotherapeutic drugs induce noncanonical processing and release of IL-1β via caspase-8 in dendritic cells. J. Immunol. 191:4789–803 [Google Scholar]
  134. Shenderov K, Riteau N, Yip R, Mayer-Barber KD, Oland S. 134.  et al. 2014. Cutting edge: Endoplasmic reticulum stress licenses macrophages to produce mature IL-1β in response to TLR4 stimulation through a caspase-8– and TRIF-dependent pathway. J. Immunol. 192:2029–33 [Google Scholar]
  135. Man SM, Tourlomousis P, Hopkins L, Monie TP, Fitzgerald KA, Bryant CE. 135.  2013. Salmonella infection induces recruitment of caspase-8 to the inflammasome to modulate IL-1β production. J. Immunol. 191:5239–46 [Google Scholar]
  136. Gurung P, Anand PK, Malireddi RKS, Vande Walle L, Van Opdenbosch N. 136.  et al. 2014. FADD and caspase-8 mediate priming and activation of the canonical and noncanonical Nlrp3 inflammasomes. J. Immunol. 192:1835–46 [Google Scholar]
  137. Vince JE, Wong WW, Gentle I, Lawlor KE, Allam R. 137.  et al. 2012. Inhibitor of apoptosis proteins limit RIP3 kinase-dependent interleukin-1 activation. Immunity 36:215–27 [Google Scholar]
  138. Young JA, He TH, Reizis B, Winoto A. 138.  2013. Commensal microbiota are required for systemic inflammation triggered by necrotic dendritic cells. Cell Rep. 27:1932–44 [Google Scholar]
  139. Kang TB, Yang SH, Toth B, Kovalenko A, Wallach D. 139.  2013. Caspase-8 blocks kinase RIPK3-mediated activation of the NLRP3 inflammasome. Immunity 38:27–40 [Google Scholar]
  140. Alappat EC, Feig C, Boyerinas B, Volkland J, Samuels M. 140.  et al. 2005. Phosphorylation of FADD at serine 194 by CKIα regulates its nonapoptotic activities. Mol. Cell 19:321–32 [Google Scholar]
  141. Hua ZC, Sohn SJ, Kang C, Cado D, Winoto A. 141.  2003. A function of Fas-associated death domain protein in cell cycle progression localized to a single amino acid at its C-terminal region. Immunity 18:513–21 [Google Scholar]
  142. Osborn SL, Sohn SJ, Winoto A. 142.  2007. Constitutive phosphorylation mutation in Fas-associated death domain (FADD) results in early cell cycle defects. J. Biol. Chem. 282:22786–92 [Google Scholar]
  143. Zermati Y, Garrido C, Amsellem S, Fishelson S, Bouscary D. 143.  et al. 2001. Caspase activation is required for terminal erythroid differentiation. J. Exp. Med. 193:247–54 [Google Scholar]
  144. Lee P, Lee DJ, Chan C, Chen SW, Ch'en I, Jamora C. 144.  2009. Dynamic expression of epidermal caspase-8 simulates a wound healing response. Nature 458:519–23 [Google Scholar]
  145. Hyman BT, Yuan J. 145.  2012. Apoptotic and non-apoptotic roles of caspases in neuronal physiology and pathophysiology. Nat. Rev. Neurosci. 13:395–406 [Google Scholar]
  146. Upton JW, Chan FKM. 146.  2014. Staying alive: cell death in antiviral immunity. Mol. Cell 54:273–80 [Google Scholar]
  147. Polykratis A, Hermance N, Zelic M, Roderick J, Kim C. 147.  et al. 2014. Cutting edge: RIPK1 kinase inactive mice are viable and protected from TNF-induced necroptosis in vivo. J. Immunol. 93:1539–43 [Google Scholar]
  148. Kotwal GJ, Moss B. 148.  1988. Analysis of a large cluster of nonessential genes deleted from a vaccinia virus terminal transposition mutant. Virology 167:524–37 [Google Scholar]
  149. Lembo D, Brune W. 149.  2009. Tinkering with a viral ribonucleotide reductase. Trends Biochem. Sci. 34:25–32 [Google Scholar]
  150. Linkermann A, Bräsen JH, De Zen F, Weinlich R, Schwendener RA. 150.  et al. 2012. Dichotomy between RIP1- and RIP3-mediated necroptosis in tumor necrosis factor-α-induced shock. Mol. Med. 18:577–86 [Google Scholar]
  151. Duprez L, Takahashi N, Van Hauwermeiren F, Vandendriessche B, Goossens V. 151.  et al. 2011. RIP kinase-dependent necrosis drives lethal systemic inflammatory response syndrome. Immunity 35:908–18 [Google Scholar]
  152. Harris PA, Bandyopadhyay D, Berger SB, Campobasso N, Capriotti CA. 152.  et al. 2013. Discovery of small molecule RIP1 kinase inhibitors for the treatment of pathologies associated with necroptosis. ACS Med. Chem. Lett. 4:1238–43 [Google Scholar]
  153. Wu J, Huang Z, Ren J, Zhang Z, He P. 153.  et al. 2013. Mlkl knockout mice demonstrate the indispensable role of Mlkl in necroptosis. Cell Res. 23:994–1006 [Google Scholar]
  154. Philip NH, Dillon CP, Snyder AG, Fitzgerald P, Wynosky-Dolfi MA. 154.  et al. 2014. Caspase-8 mediates caspase-1 processing and innate immune defense in response to bacterial blockade of NF-κB and MAPK signaling. PNAS 111:7385–90 [Google Scholar]
  155. Weng D, Marty-Roix R, Ganesan S, Proulx MK, Vladimer GI. 155.  et al. 2014. Caspase-8 and RIP kinases regulate bacteria-induced innate immune responses and cell death. PNAS 111:7391–96 [Google Scholar]
  156. Broz P, Ruby T, Belhocine K, Bouley DM, Kayagaki N. 156.  et al. 2012. Caspase-11 increases susceptibility to Salmonella infection in the absence of caspase-1. Nature 490:288–91 [Google Scholar]
  157. Robinson N, McComb S, Mulligan R, Dudani R, Krishnan L, Sad S. 157.  2012. Type I interferon induces necroptosis in macrophages during infection with Salmonella enterica serovar Typhimurium. Nat. Immunol. 13:954–62 [Google Scholar]
  158. Roca FJ, Ramakrishnan L. 158.  2013. TNF dually mediates resistance and susceptibility to mycobacteria via mitochondrial reactive oxygen species. Cell 153:521–34 [Google Scholar]
  159. Divangahi M, Behar SM, Remold H. 159.  2013. Dying to live: how the death modality of the infected macrophage affects immunity to tuberculosis. Adv. Exp. Med. Biol. 783:103–20 [Google Scholar]
  160. Nakagawa T, Shimizu S, Watanabe T, Yamaguchi O, Otsu K. 160.  et al. 2005. Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 434:652–58 [Google Scholar]
  161. Linkermann A, Bräsen JH, Darding M, Jin MK, Sanz AB. 161.  et al. 2013. Two independent pathways of regulated necrosis mediate ischemia-reperfusion injury. PNAS 110:12024–29 [Google Scholar]
  162. Chiabrando D, Vinchi F, Fiorito V, Mercurio S, Tolosano E. 162.  2014. Heme in pathophysiology: a matter of scavenging, metabolism and trafficking across cell membranes. Front. Pharmacol. 5:61 [Google Scholar]
  163. Seixas E, Gozzelino R, Chora A, Ferreira A, Silva G. 163.  et al. 2009. Heme oxygenase-1 affords protection against noncerebral forms of severe malaria. PNAS 106:15837–42 [Google Scholar]
  164. Fortes GB, Alves LS, de Oliveira R, Dutra FF, Rodrigues D. 164.  et al. 2012. Heme induces programmed necrosis on macrophages through autocrine TNF and ROS production. Blood 119:2368–75 [Google Scholar]
  165. Roychowdhury S, McMullen MR, Pisano SG, Liu X, Nagy LE. 165.  2013. Absence of receptor interacting protein kinase 3 prevents ethanol-induced liver injury. Hepatology 57:1773–83 [Google Scholar]
  166. Ramachandran A, McGill MR, Xie Y, Ni HM, Ding WX, Jaeschke H. 166.  2013. Receptor interacting protein kinase 3 is a critical early mediator of acetaminophen-induced hepatocyte necrosis in mice. Hepatology 58:2099–108 [Google Scholar]
  167. Malleo G, Mazzon E, Genovese T, Di Paola R, Muia C. 167.  et al. 2007. Etanercept attenuates the development of cerulein-induced acute pancreatitis in mice: a comparison with TNF-α genetic deletion. Shock 27:542–51 [Google Scholar]
  168. He S, Wang L, Miao L, Du F, Zhao L, Wang X. 168.  2009. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-α. Cell 137:1100–11 [Google Scholar]
  169. Vitner EB, Salomon R, Farfel-Becker T, Meshcheriakova A, Ali M. 169.  et al. 2014. RIPK3 as a potential therapeutic target for Gaucher's disease. Nat. Med. 20:204–8 [Google Scholar]
  170. Smith CC, Davidson SM, Lim SY, Simpkin JC, Hothersall JS, Yellon DM. 170.  2007. Necrostatin: a potentially novel cardioprotective agent?. Cardiovasc. Drugs Ther. 21:227–33 [Google Scholar]
  171. Luedde M, Lutz M, Carter N, Sosna J, Jacoby C. 171.  et al. 2014. RIP3, a kinase promoting necroptotic cell death, mediates adverse remodelling after myocardial infarction. Cardiovasc. Res. 103:206–16 [Google Scholar]
  172. Vandenabeele P, Grootjans S, Callewaert N, Takahashi N. 172.  2013. Necrostatin-1 blocks both RIPK1 and IDO: consequences for the study of cell death in experimental disease models. Cell Death Differ. 20:185–87 [Google Scholar]
  173. Tabas I. 173.  2010. Macrophage death and defective inflammation resolution in atherosclerosis. Nat. Rev. Immunol. 10:36–46 [Google Scholar]
  174. Lin J, Li H, Yang M, Ren J, Huang Z. 174.  et al. 2013. A role of RIP3-mediated macrophage necrosis in atherosclerosis development. Cell Rep. 3:200–10 [Google Scholar]
  175. Trichonas G, Murakami Y, Thanos A, Morizane Y, Kayama M. 175.  et al. 2010. Receptor interacting protein kinases mediate retinal detachment-induced photoreceptor necrosis and compensate for inhibition of apoptosis. PNAS 107:21695–700 [Google Scholar]
  176. Murakami Y, Matsumoto H, Roh M, Suzuki J, Hisatomi T. 176.  et al. 2012. Receptor interacting protein kinase mediates necrotic cone but not rod cell death in a mouse model of inherited degeneration. PNAS 109:14598–603 [Google Scholar]
  177. Murakami Y, Matsumoto H, Roh M, Giani A, Kataoka K. 177.  et al. 2014. Programmed necrosis, not apoptosis, is a key mediator of cell loss and DAMP-mediated inflammation in dsRNA-induced retinal degeneration. Cell Death Differ. 21:270–77 [Google Scholar]
  178. Viringipurampeer IA, Shan X, Gregory-Evans K, Zhang JP, Mohammadi Z, Gregory-Evans CY. 178.  2014. Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish. Cell Death Differ. 21:665–75 [Google Scholar]
  179. Kleino A, Silverman N. 179.  2014. The Drosophila IMD pathway in the activation of the humoral immune response. Dev. Comp. Immunol. 42:25–35 [Google Scholar]
  180. Kaneko T, Yano T, Aggarwal K, Lim JH, Ueda K. 180.  et al. 2006. PGRP-LC and PGRP-LE have essential yet distinct functions in the drosophila immune response to monomeric DAP-type peptidoglycan. Nat. Immunol. 7:715–23 [Google Scholar]
  181. Georgel P, Naitza S, Kappler C, Ferrandon D, Zachary D. 181.  et al. 2001. Drosophila immune deficiency (IMD) is a death domain protein that activates antibacterial defense and can promote apoptosis. Dev. Cell 1:503–14 [Google Scholar]
  182. Kanda H, Igaki T, Okano H, Miura M. 182.  2011. Conserved metabolic energy production pathways govern Eiger/TNF-induced nonapoptotic cell death. PNAS 108:18977–82 [Google Scholar]
  183. Obata F, Kuranaga E, Tomioka K, Ming M, Takeishi A. 183.  et al. 2014. Necrosis-driven systemic immune response alters SAM metabolism through the FOXO-GNMT axis. Cell Rep. 7:821–33 [Google Scholar]
  184. Jenkins VK, Timmons AK, McCall K. 184.  2013. Diversity of cell death pathways: insight from the fly ovary. Trends Cell Biol. 23:567–74 [Google Scholar]
  185. Kuang C, Golden KL, Simon CR, Damrath J, Buttitta L. 185.  et al. 2014. A novel Fizzy/Cdc20-dependent mechanism suppresses necrosis in neural stem cells. Development 141:1453–64 [Google Scholar]
  186. Vilella AJ, Severin J, Ureta-Vidal A, Heng L, Durbin R, Birney E. 186.  2009. EnsemblCompara GeneTrees: complete, duplication-aware phylogenetic trees in vertebrates. Genome Res. 19:327–35 [Google Scholar]
  187. Kovalenko A, Kim JC, Kang TB, Rajput A, Bogdanov K. 187.  et al. 2009. Caspase-8 deficiency in epidermal keratinocytes triggers an inflammatory skin disease. J. Exp. Med. 206:2161–77 [Google Scholar]
  188. Linkermann A, Bräsen JH, Himmerkus N, Liu S, Huber TB. 188.  et al. 2012. Rip1 (receptor-interacting protein kinase 1) mediates necroptosis and contributes to renal ischemia/reperfusion injury. Kidney Int. 81:751–61 [Google Scholar]
  189. Zhang DW, Shao J, Lin J, Zhang N, Lu BJ. 189.  et al. 2009. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 325:332–36 [Google Scholar]
/content/journals/10.1146/annurev-immunol-032414-112248
Loading
/content/journals/10.1146/annurev-immunol-032414-112248
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error