Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

RIP kinases as modulators of inflammation and immunity

Nature Immunology volume 19, pages 912–922 (2018)Cite this article

Subjects

Abstract

Receptor-interacting protein (RIP) kinases, in particular RIPK1, RIPK2 and RIPK3, have emerged as pleiotropic modulators of inflammatory responses that act either by directly regulating intracellular inflammatory signaling pathways or by causing apoptotic or necrotic cell death. In this Review, we discuss the signaling pathways and immunological functions of these RIP kinases in the inflammatory response to microbial infection and tissue injury, as well as their potential roles in the pathogenesis of inflammatory disease and aging.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The domain structure of members of the RIP kinase family.
Fig. 2: The necroptosis signaling pathway.
Fig. 3: Molecular cross-talk among apoptosis, pyroptosis and necroptosis.

Similar content being viewed by others

References

  1. Stanger, B. Z., Leder, P., Lee, T. H., Kim, E. & Seed, B. RIP: a novel protein containing a death domain that interacts with Fas/APO-1 (CD95) in yeast and causes cell death. Cell 81, 513–523 (1995).

    Article  PubMed  CAS  Google Scholar 

  2. Kerr, J. F., Wyllie, A. H. & Currie, A. R. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26, 239–257 (1972).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Peter, M. E. & Krammer, P. H. The CD95(APO-1/Fas) DISC and beyond. Cell Death Differ. 10, 26–35 (2003).

    Article  PubMed  CAS  Google Scholar 

  4. Ashkenazi, A. & Dixit, V. M. Death receptors: signaling and modulation. Science 281, 1305–1308 (1998).

    Article  PubMed  CAS  Google Scholar 

  5. Micheau, O. & Tschopp, J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 114, 181–190 (2003).

    Article  PubMed  CAS  Google Scholar 

  6. Wang, C. Y., Mayo, M. W., Korneluk, R. G., Goeddel, D. V. & Baldwin, A. S. Jr. NF-κB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science 281, 1680–1683 (1998).

    Article  PubMed  CAS  Google Scholar 

  7. Thome, M. et al. Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature 386, 517–521 (1997).

    Article  PubMed  CAS  Google Scholar 

  8. Lee, H. H., Dadgostar, H., Cheng, Q., Shu, J. & Cheng, G. NF-κB-mediated up-regulation of Bcl-x and Bfl-1/A1 is required for CD40 survival signaling in B lymphocytes. Proc. Natl. Acad. Sci. USA 96, 9136–9141 (1999).

  9. Tamatani, M. et al. Tumor necrosis factor induces Bcl-2 and Bcl-x expression through NFκB activation in primary hippocampal neurons. J. Biol. Chem. 274, 8531–8538 (1999).

    Article  PubMed  CAS  Google Scholar 

  10. Wang, L., Du, F. & Wang, X. TNF-α induces two distinct caspase-8 activation pathways. Cell 133, 693–703 (2008).

    Article  PubMed  CAS  Google Scholar 

  11. Li, P. et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91, 479–489 (1997).

    Article  PubMed  CAS  Google Scholar 

  12. Yang, Q. H. & Du, C. Smac/DIABLO selectively reduces the levels of c-IAP1 and c-IAP2 but not that of XIAP and livin in HeLa cells. J. Biol. Chem. 279, 16963–16970 (2004).

    Article  PubMed  CAS  Google Scholar 

  13. Petersen, S. L. et al. Autocrine TNFα signaling renders human cancer cells susceptible to Smac-mimetic-induced apoptosis. Cancer Cell 12, 445–456 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Li, L. et al. A small molecule Smac mimic potentiates TRAIL- and TNFα-mediated cell death. Science 305, 1471–1474 (2004).

    Article  PubMed  CAS  Google Scholar 

  15. Vince, J. E. et al. IAP antagonists target cIAP1 to induce TNFα-dependent apoptosis. Cell 131, 682–693 (2007).

    Article  PubMed  CAS  Google Scholar 

  16. Varfolomeev, E. et al. IAP antagonists induce autoubiquitination of c-IAPs, NF-κB activation, and TNFα-dependent apoptosis. Cell 131, 669–681 (2007).

    Article  PubMed  CAS  Google Scholar 

  17. Kreuz, S., Siegmund, D., Scheurich, P. & Wajant, H. NF-κB inducers upregulate cFLIP, a cycloheximide-sensitive inhibitor of death receptor signaling. Mol. Cell. Biol. 21, 3964–3973 (2001).

  18. Laster, S. M., Wood, J. G. & Gooding, L. R. Tumor necrosis factor can induce both apoptic and necrotic forms of cell lysis. J. Immunol. 141, 2629–2634 (1988).

    PubMed  CAS  Google Scholar 

  19. Holler, N. et al. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat. Immunol. 1, 489–495 (2000).

    Article  PubMed  CAS  Google Scholar 

  20. Chan, F. K. M. et al. A role for tumor necrosis factor receptor-2 and receptor-interacting protein in programmed necrosis and antiviral responses. J. Biol. Chem. 278, 51613–51621 (2003).

    Article  PubMed  CAS  Google Scholar 

  21. Degterev, A. et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat. Chem. Biol. 1, 112–119 (2005).

    Article  PubMed  CAS  Google Scholar 

  22. Degterev, A. et al. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat. Chem. Biol. 4, 313–321 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Sun, X., Yin, J., Starovasnik, M. A., Fairbrother, W. J. & Dixit, V. M. Identification of a novel homotypic interaction motif required for the phosphorylation of receptor-interacting protein (RIP) by RIP3. J. Biol. Chem. 277, 9505–9511 (2002).

    Article  PubMed  CAS  Google Scholar 

  24. Meylan, E. et al. RIP1 is an essential mediator of Toll-like receptor 3-induced NF-κB activation. Nat. Immunol. 5, 503–507 (2004).

  25. Kaiser, W. J., Upton, J. W. & Mocarski, E. S. Receptor-interacting protein homotypic interaction motif-dependent control of NF-kappa B activation via the DNA-dependent activator of IFN regulatory factors. J. Immunol. 181, 6427–6434 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. He, S. et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-α. Cell 137, 1100–1111 (2009).

  27. Cho, Y. S. et al. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 137, 1112–1123 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Zhang, D. W. et al. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 325, 332–336 (2009).

    Article  PubMed  CAS  Google Scholar 

  29. Li, J. et al. The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. Cell 150, 339–350 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Robinson, N. et al. Type I interferon induces necroptosis in macrophages during infection with Salmonella enterica serovar Typhimurium. Nat. Immunol. 13, 954–962 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Thapa, R. J. et al. Interferon-induced RIP1/RIP3-mediated necrosis requires PKR and is licensed by FADD and caspases. Proc. Natl. Acad. Sci. USA 110, E3109–E3118 (2013).

  32. He, S., Liang, Y., Shao, F. & Wang, X. Toll-like receptors activate programmed necrosis in macrophages through a receptor-interacting kinase-3-mediated pathway. Proc. Natl. Acad. Sci. USA 108, 20054–20059 (2011).

  33. Upton, J. W., Kaiser, W. J. & Mocarski, E. S. DAI/ZBP1/DLM-1 complexes with RIP3 to mediate virus-induced programmed necrosis that is targeted by murine cytomegalovirus vIRA. Cell Host Microbe 11, 290–297 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Gay, N. J., Symmons, M. F., Gangloff, M. & Bryant, C. E. Assembly and localization of Toll-like receptor signalling complexes. Nat. Rev. Immunol. 14, 546–558 (2014).

    Article  PubMed  CAS  Google Scholar 

  35. Kaiser, W. J. et al. Toll-like receptor 3-mediated necrosis via TRIF, RIP3, and MLKL. J. Biol. Chem. 288, 31268–31279 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Takaoka, A. et al. DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature 448, 501–505 (2007).

    Article  PubMed  CAS  Google Scholar 

  37. Sun, X. et al. RIP3, a novel apoptosis-inducing kinase. J. Biol. Chem. 274, 16871–16875 (1999).

    Article  PubMed  CAS  Google Scholar 

  38. Yu, P. W. et al. Identification of RIP3, a RIP-like kinase that activates apoptosis and NFκB. Curr. Biol. 9, 539–542 (1999).

    Article  PubMed  CAS  Google Scholar 

  39. Kasof, G. M., Prosser, J. C., Liu, D., Lorenzi, M. V. & Gomes, B. C. The RIP-like kinase, RIP3, induces apoptosis and NF-κB nuclear translocation and localizes to mitochondria. FEBS Lett. 473, 285–291 (2000).

    Article  PubMed  CAS  Google Scholar 

  40. Newton, K. et al. Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosis. Science 343, 1357–1360 (2014).

    Article  PubMed  CAS  Google Scholar 

  41. Mandal, P. et al. RIP3 induces apoptosis independent of pronecrotic kinase activity. Mol. Cell 56, 481–495 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Nogusa, S. et al. RIPK3 activates parallel pathways of MLKL-driven necroptosis and FADD-mediated apoptosis to protect against influenza A virus. Cell Host Microbe 20, 13–24 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Kuriakose, T. et al. ZBP1/DAI is an innate sensor of influenza virus triggering the NLRP3 inflammasome and programmed cell death pathways. Sci. Immunol. 1, aag2045 (2016).

    Article  PubMed Central  PubMed  Google Scholar 

  44. Sun, L. et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell 148, 213–227 (2012).

    Article  PubMed  CAS  Google Scholar 

  45. Zhao, J. et al. Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis. Proc. Natl. Acad. Sci. USA 109, 5322–5327 (2012).

  46. Manning, G., Whyte, D. B., Martinez, R., Hunter, T. & Sudarsanam, S. The protein kinase complement of the human genome. Science 298, 1912–1934 (2002).

    Article  PubMed  CAS  Google Scholar 

  47. Murphy, J. M. et al. The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism. Immunity 39, 443–453 (2013).

    Article  PubMed  CAS  Google Scholar 

  48. Rodriguez, D. A. et al. Characterization of RIPK3-mediated phosphorylation of the activation loop of MLKL during necroptosis. Cell Death Differ. 23, 76–88 (2016).

    Article  PubMed  CAS  Google Scholar 

  49. Wang, H. et al. Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol. Cell 54, 133–146 (2014).

    Article  PubMed  CAS  Google Scholar 

  50. Cai, Z. et al. Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis. Nat. Cell Biol. 16, 55–65 (2014).

    Article  PubMed  CAS  Google Scholar 

  51. Chen, X. et al. Translocation of mixed lineage kinase domain-like protein to plasma membrane leads to necrotic cell death. Cell Res. 24, 105–121 (2014).

    Article  PubMed  CAS  Google Scholar 

  52. Dondelinger, Y. et al. MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates. Cell Rep. 7, 971–981 (2014).

  53. Dovey, C. M. et al. MLKL requires the inositol phosphate code to execute necroptosis. Mol. Cell 70, 936–948 (2018).

    Article  PubMed  CAS  Google Scholar 

  54. Hildebrand, J. M. et al. Activation of the pseudokinase MLKL unleashes the four-helix bundle domain to induce membrane localization and necroptotic cell death. Proc. Natl. Acad. Sci. USA 111, 15072–15077 (2014).

  55. Xia, B. et al. MLKL forms cation channels. Cell Res. 26, 517–528 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Feng, S. et al. Cleavage of RIP3 inactivates its caspase-independent apoptosis pathway by removal of kinase domain. Cell. Signal. 19, 2056–2067 (2007).

    Article  PubMed  CAS  Google Scholar 

  57. Kaiser, W. J. et al. RIP3 mediates the embryonic lethality of caspase-8-deficient mice. Nature 471, 368–372 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Oberst, A. et al. Catalytic activity of the caspase-8-FLIP(L) complex inhibits RIPK3-dependent necrosis. Nature 471, 363–367 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Dillon, C. P. et al. Survival function of the FADD-CASPASE-8-cFLIP(L) complex. Cell Rep. 1, 401–407 (2012).

  60. Wilson, N. S., Dixit, V. & Ashkenazi, A. Death receptor signal transducers: nodes of coordination in immune signaling networks. Nat. Immunol. 10, 348–355 (2009).

    Article  PubMed  CAS  Google Scholar 

  61. Newton, K., Sun, X. & Dixit, V. M. 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, 1464–1469 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Wu, J. et al. Mlkl knockout mice demonstrate the indispensable role of Mlkl in necroptosis. Cell Res. 23, 994–1006 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Haas, T. L. et al. Recruitment of the linear ubiquitin chain assembly complex stabilizes the TNF-R1 signaling complex and is required for TNF-mediated gene induction. Mol. Cell 36, 831–844 (2009).

    Article  PubMed  CAS  Google Scholar 

  64. Wright, A. et al. Regulation of early wave of germ cell apoptosis and spermatogenesis by deubiquitinating enzyme CYLD. Dev. Cell 13, 705–716 (2007).

    Article  PubMed  CAS  Google Scholar 

  65. Wertz, I. E. et al. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-κB signalling. Nature 430, 694–699 (2004).

    Article  PubMed  CAS  Google Scholar 

  66. Hitomi, J. et al. Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell 135, 1311–1323 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Biton, S. & Ashkenazi, A. NEMO and RIP1 control cell fate in response to extensive DNA damage via TNF-α feedforward signaling. Cell 145, 92–103 (2011).

    Article  PubMed  CAS  Google Scholar 

  68. Chen, W. et al. Ppm1b negatively regulates necroptosis through dephosphorylating Rip3. Nat. Cell Biol. 17, 434–444 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Onizawa, M. et al. The ubiquitin-modifying enzyme A20 restricts ubiquitination of the kinase RIPK3 and protects cells from necroptosis. Nat. Immunol. 16, 618–627 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Wang, H. et al. PELI1 functions as a dual modulator of necroptosis and apoptosis by regulating ubiquitination of RIPK1 and mRNA levels of c-FLIP. Proc. Natl. Acad. Sci. USA 114, 11944–11949 (2017).

  71. Gong, Y. N. et al. ESCRT-III acts downstream of MLKL to regulate necroptotic cell death and its consequences. Cell 169, 286–300 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Yoon, S., Kovalenko, A., Bogdanov, K. & Wallach, D. MLKL, the protein that mediates necroptosis, also regulates endosomal trafficking and extracellular vesicle generation. Immunity 47, 51–65 (2017).

    Article  PubMed  CAS  Google Scholar 

  73. Zargarian, S. et al. Phosphatidylserine externalization, “necroptotic bodies” release, and phagocytosis during necroptosis. PLoS Biol. 15, e2002711 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Rickard, J. A. et al. RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis. Cell 157, 1175–1188 (2014).

    Article  PubMed  CAS  Google Scholar 

  75. Dillon, C. P. et al. RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3. Cell 157, 1189–1202 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Kaiser, W. J. et al. RIP1 suppresses innate immune necrotic as well as apoptotic cell death during mammalian parturition. Proc. Natl. Acad. Sci. USA 111, 7753–7758 (2014).

  77. Kelliher, M. A. et al. The death domain kinase RIP mediates the TNF-induced NF-κB signal. Immunity 8, 297–303 (1998).

    Article  PubMed  CAS  Google Scholar 

  78. Berger, S. B. et al. Cutting Edge: RIP1 kinase activity is dispensable for normal development but is a key regulator of inflammation in SHARPIN-deficient mice. J. Immunol. 192, 5476–5480 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Newton, K. et al. RIPK1 inhibits ZBP1-driven necroptosis during development. Nature 540, 129–133 (2016).

    Article  PubMed  CAS  Google Scholar 

  80. Lin, J. et al. RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation. Nature 540, 124–128 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Welz, P. S. et al. FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation. Nature 477, 330–334 (2011).

    Article  PubMed  CAS  Google Scholar 

  82. Günther, C. et al. Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis. Nature 477, 335–339 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Weinlich, R. et al. Protective roles for caspase-8 and cFLIP in adult homeostasis. Cell Rep. 5, 340–348 (2013).

  84. Bonnet, M. C. et al. The adaptor protein FADD protects epidermal keratinocytes from necroptosis in vivo and prevents skin inflammation. Immunity 35, 572–582 (2011).

    Article  PubMed  CAS  Google Scholar 

  85. Dannappel, M. et al. RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis. Nature 513, 90–94 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Pierdomenico, M. et al. Necroptosis is active in children with inflammatory bowel disease and contributes to heighten intestinal inflammation. Am. J. Gastroenterol. 109, 279–287 (2014).

    Article  PubMed  CAS  Google Scholar 

  87. Duprez, L. et al. RIP kinase-dependent necrosis drives lethal systemic inflammatory response syndrome. Immunity 35, 908–918 (2011).

    Article  PubMed  CAS  Google Scholar 

  88. Sharma, A., Matsuo, S., Yang, W. L., Wang, Z. & Wang, P. Receptor-interacting protein kinase 3 deficiency inhibits immune cell infiltration and attenuates organ injury in sepsis. Crit. Care 18, R142 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Newton, K. et al. RIPK3 deficiency or catalytically inactive RIPK1 provides greater benefit than MLKL deficiency in mouse models of inflammation and tissue injury. Cell Death Differ. 23, 1565–1576 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Lin, J. et al. A role of RIP3-mediated macrophage necrosis in atherosclerosis development. Cell Rep. 3, 200–210 (2013).

  91. Meng, L., Jin, W. & Wang, X. RIP3-mediated necrotic cell death accelerates systematic inflammation and mortality. Proc. Natl. Acad. Sci. USA 112, 11007–11012 (2015).

  92. Liu, Z. Y. et al. Necrostatin-1 reduces intestinal inflammation and colitis-associated tumorigenesis in mice. Am. J. Cancer Res. 5, 3174–3185 (2015).

    PubMed  PubMed Central  CAS  Google Scholar 

  93. Mizumura, K. et al. Mitophagy-dependent necroptosis contributes to the pathogenesis of COPD. J. Clin. Invest. 124, 3987–4003 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Pouwels, S. D. et al. Cigarette smoke-induced necroptosis and DAMP release trigger neutrophilic airway inflammation in mice. Am. J. Physiol. Lung Cell. Mol. Physiol. 310, L377–L386 (2016).

    Article  PubMed  Google Scholar 

  95. Lawlor, K. E. et al. RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL. Nat. Commun. 6, 6282 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Roychowdhury, S., McMullen, M. R., Pisano, S. G., Liu, X. & Nagy, L. E. Absence of receptor interacting protein kinase 3 prevents ethanol-induced liver injury. Hepatology 57, 1773–1783 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Gautheron, J. et al. A positive feedback loop between RIP3 and JNK controls non-alcoholic steatohepatitis. EMBO Mol. Med. 6, 1062–1074 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Lau, A. et al. RIPK3-mediated necroptosis promotes donor kidney inflammatory injury and reduces allograft survival. Am. J. Transplant. 13, 2805–2818 (2013).

    Article  PubMed  CAS  Google Scholar 

  99. Pavlosky, A. et al. RIPK3-mediated necroptosis regulates cardiac allograft rejection. Am. J. Transplant. 14, 1778–1790 (2014).

    Article  PubMed  CAS  Google Scholar 

  100. Linkermann, A. et al. Two independent pathways of regulated necrosis mediate ischemia-reperfusion injury. Proc. Natl. Acad. Sci. USA 110, 12024–12029 (2013).

  101. Luedde, M. et al. RIP3, a kinase promoting necroptotic cell death, mediates adverse remodelling after myocardial infarction. Cardiovasc. Res. 103, 206–216 (2014).

    Article  PubMed  CAS  Google Scholar 

  102. Zhang, T. et al. CaMKII is a RIP3 substrate mediating ischemia- and oxidative stress-induced myocardial necroptosis. Nat. Med. 22, 175–182 (2016).

    Article  PubMed  CAS  Google Scholar 

  103. Dara, L., Liu, Z. X. & Kaplowitz, N. Questions and controversies: the role of necroptosis in liver disease. Cell Death Discov. 2, 16089 (2016).

  104. Yatim, N. et al. RIPK1 and NF-κB signaling in dying cells determines cross-priming of CD8+ T cells. Science 350, 328–334 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Schmidt, S. V. et al. RIPK3 expression in cervical cancer cells is required for PolyIC-induced necroptosis, IL-1α release, and efficient paracrine dendritic cell activation. Oncotarget 6, 8635–8647 (2015).

    PubMed  PubMed Central  Google Scholar 

  106. Murakami, Y. et al. Programmed necrosis, not apoptosis, is a key mediator of cell loss and DAMP-mediated inflammation in dsRNA-induced retinal degeneration. Cell Death Differ. 21, 270–277 (2014).

    Article  PubMed  CAS  Google Scholar 

  107. Aaes, T. L. et al. Vaccination with necroptotic cancer cells induces efficient anti-tumor immunity. Cell Rep. 15, 274–287 (2016).

  108. Ea, C. K., Deng, L., Xia, Z. P., Pineda, G. & Chen, Z. J. Activation of IKK by TNFα requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO. Mol. Cell 22, 245–257 (2006).

    Article  PubMed  CAS  Google Scholar 

  109. Kanayama, A. et al. TAB2 and TAB3 activate the NF-κB pathway through binding to polyubiquitin chains. Mol. Cell 15, 535–548 (2004).

    Article  PubMed  CAS  Google Scholar 

  110. Hur, G. M. et al. The death domain kinase RIP has an essential role in DNA damage-induced NF-κB activation. Genes Dev. 17, 873–882 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Janssens, S., Tinel, A., Lippens, S. & Tschopp, J. PIDD mediates NF-κB activation in response to DNA damage. Cell 123, 1079–1092 (2005).

    Article  PubMed  CAS  Google Scholar 

  112. Wong, W. W. et al. cIAPs and XIAP regulate myelopoiesis through cytokine production in an RIPK1- and RIPK3-dependent manner. Blood 123, 2562–2572 (2014).

    Article  PubMed  CAS  Google Scholar 

  113. Wang, X. et al. RNA viruses promote activation of the NLRP3 inflammasome through a RIP1-RIP3-DRP1 signaling pathway. Nat. Immunol. 15, 1126–1133 (2014).

    Article  PubMed  CAS  Google Scholar 

  114. Najjar, M. et al. RIPK1 and RIPK3 kinases promote cell-death-independent inflammation by Toll-like receptor 4. Immunity 45, 46–59 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Moriwaki, K., Bertin, J., Gough, P. J. & Chan, F. K. A. A RIPK3-caspase 8 complex mediates atypical pro-IL-1β processing. J. Immunol. 194, 1938–1944 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Höckendorf, U., Yabal, M. & Jost, P. J. RIPK3-dependent cell death and inflammasome activation in FLT3-ITD expressing LICs. Oncotarget 7, 57483–57484 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Vince, J. E. et al. Inhibitor of apoptosis proteins limit RIP3 kinase-dependent interleukin-1 activation. Immunity 36, 215–227 (2012).

    Article  PubMed  CAS  Google Scholar 

  118. Kang, T. B., Yang, S. H., Toth, B., Kovalenko, A. & Wallach, D. Caspase-8 blocks kinase RIPK3-mediated activation of the NLRP3 inflammasome. Immunity 38, 27–40 (2013).

    Article  PubMed  CAS  Google Scholar 

  119. Moriwaki, K. et al. The necroptosis adaptor RIPK3 promotes injury-induced cytokine expression and tissue repair. Immunity 41, 567–578 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Lukens, J. R. et al. RIP1-driven autoinflammation targets IL-1α independently of inflammasomes and RIP3. Nature 498, 224–227 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Kang, S. et al. Caspase-8 scaffolding function and MLKL regulate NLRP3 inflammasome activation downstream of TLR3. Nat. Commun. 6, 7515 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Lamkanfi, M. & Dixit, V. M. Mechanisms and functions of inflammasomes. Cell 157, 1013–1022 (2014).

    Article  PubMed  CAS  Google Scholar 

  123. Miwa, K. et al. Caspase 1-independent IL-1β release and inflammation induced by the apoptosis inducer Fas ligand. Nat. Med. 4, 1287–1292 (1998).

    Article  PubMed  CAS  Google Scholar 

  124. Inohara, N., del Peso, L., Koseki, T., Chen, S. & Núñez, G. RICK, a novel protein kinase containing a caspase recruitment domain, interacts with CLARP and regulates CD95-mediated apoptosis. J. Biol. Chem. 273, 12296–12300 (1998).

    Article  PubMed  CAS  Google Scholar 

  125. McCarthy, J. V., Ni, J. & Dixit, V. M. RIP2 is a novel NF-κB-activating and cell death-inducing kinase. J. Biol. Chem. 273, 16968–16975 (1998).

    Article  PubMed  CAS  Google Scholar 

  126. Thome, M. et al. Identification of CARDIAK, a RIP-like kinase that associates with caspase-1. Curr. Biol. 8, 885–888 (1998).

    Article  PubMed  CAS  Google Scholar 

  127. Navas, T. A., Baldwin, D. T. & Stewart, T. A. RIP2 is a Raf1-activated mitogen-activated protein kinase kinase. J. Biol. Chem. 274, 33684–33690 (1999).

    Article  PubMed  CAS  Google Scholar 

  128. Caruso, R., Warner, N., Inohara, N. & Núñez, G. NOD1 and NOD2: signaling, host defense, and inflammatory disease. Immunity 41, 898–908 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Inohara, N. et al. Nod1, an Apaf-1-like activator of caspase-9 and nuclear factor-κB. J. Biol. Chem. 274, 14560–14567 (1999).

    Article  PubMed  CAS  Google Scholar 

  130. Ogura, Y. et al. Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-κB. J. Biol. Chem. 276, 4812–4818 (2001).

    Article  PubMed  CAS  Google Scholar 

  131. Inohara, N. et al. An induced proximity model for NF-κB activation in the Nod1/RICK and RIP signaling pathways. J. Biol. Chem. 275, 27823–27831 (2000).

    PubMed  CAS  Google Scholar 

  132. Witt, A. & Vucic, D. Diverse ubiquitin linkages regulate RIP kinases-mediated inflammatory and cell death signaling. Cell Death Differ. 24, 1160–1171 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Bauler, L. D., Duckett, C. S. & O’Riordan, M. X. XIAP regulates cytosol-specific innate immunity to Listeria infection. PLoS Pathog. 4, e1000142 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Goncharov, T. et al. Disruption of XIAP-RIP2 association blocks NOD2-mediated inflammatory signaling. Mol. Cell 69, 551–565 (2018).

    Article  PubMed  CAS  Google Scholar 

  135. Damgaard, R. B. et al. The ubiquitin ligase XIAP recruits LUBAC for NOD2 signaling in inflammation and innate immunity. Mol. Cell 46, 746–758 (2012).

    Article  PubMed  CAS  Google Scholar 

  136. Hasegawa, M. et al. A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-κB activation. EMBO J. 27, 373–383 (2008).

    Article  PubMed  CAS  Google Scholar 

  137. Chin, A. I. et al. Involvement of receptor-interacting protein 2 in innate and adaptive immune responses. Nature 416, 190–194 (2002).

    Article  PubMed  CAS  Google Scholar 

  138. Kobayashi, K. et al. RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems. Nature 416, 194–199 (2002).

    Article  PubMed  CAS  Google Scholar 

  139. Li, D. et al. RIPK1-RIPK3-MLKL-dependent necrosis promotes the aging of mouse male reproductive system. eLife 6, 6 (2017).

    Google Scholar 

  140. Upton, J. W., Kaiser, W. J. & Mocarski, E. S. Virus inhibition of RIP3-dependent necrosis. Cell Host Microbe 7, 302–313 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Koehler, H. et al. Inhibition of DAI-dependent necroptosis by the Z-DNA binding domain of the vaccinia virus innate immune evasion protein, E3. Proc. Natl. Acad. Sci. USA 114, 11506–11511 (2017).

  142. Guo, H. et al. Herpes simplex virus suppresses necroptosis in human cells. Cell Host Microbe 17, 243–251 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Yu, X. et al. Herpes simplex virus 1 (HSV-1) and HSV-2 mediate species-specific modulations of programmed necrosis through the viral ribonucleotide reductase large subunit R1. J. Virol. 90, 1088–1095 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Omoto, S. et al. Suppression of RIP3-dependent necroptosis by human cytomegalovirus. J. Biol. Chem. 290, 11635–11648 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Thapa, R. J. et al. DAI senses influenza A virus genomic RNA and activates RIPK3-Dependent cell death. Cell Host Microbe 20, 674–681 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Greenlee-Wacker, M. C. et al. Phagocytosis of Staphylococcus aureus by human neutrophils prevents macrophage efferocytosis and induces programmed necrosis. J. Immunol. 192, 4709–4717 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Kitur, K. et al. Necroptosis promotes Staphylococcus aureus clearance by inhibiting excessive inflammatory signaling. Cell Rep. 16, 2219–2230 (2016).

  148. Daniels, B. P. et al. RIPK3 restricts viral pathogenesis via cell death-independent neuroinflammation. Cell 169, 301–313 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  149. Shi, J., Gao, W. & Shao, F. Pyroptosis: gasdermin-mediated programmed necrotic cell death. Trends Biochem. Sci. 42, 245–254 (2017).

    Article  PubMed  CAS  Google Scholar 

  150. Ofengeim, D. et al. Activation of necroptosis in multiple sclerosis. Cell Rep. 10, 1836–1849 (2015).

  151. Re, D. B. et al. Necroptosis drives motor neuron death in models of both sporadic and familial ALS. Neuron 81, 1001–1008 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Ito, Y. et al. RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS. Science 353, 603–608 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Caccamo, A. et al. Necroptosis activation in Alzheimer’s disease. Nat. Neurosci. 20, 1236–1246 (2017).

    Article  PubMed  CAS  Google Scholar 

  154. Ofengeim, D. et al. RIPK1 mediates a disease-associated microglial response in Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 114, E8788–E8797 (2017).

  155. Cougnoux, A. et al. Necroptosis in Niemann-Pick disease, type C1: a potential therapeutic target. Cell Death Dis. 7, e2147 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Murakami, Y. et al. Receptor interacting protein kinase mediates necrotic cone but not rod cell death in a mouse model of inherited degeneration. Proc. Natl. Acad. Sci. USA 109, 14598–14603 (2012).

  157. Sato, K. et al. Receptor interacting protein kinase-mediated necrosis contributes to cone and rod photoreceptor degeneration in the retina lacking interphotoreceptor retinoid-binding protein. J. Neurosci. 33, 17458–17468 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. Huang, Z. et al. Necroptosis in microglia contributes to neuroinflammation and retinal degeneration through TLR4 activation. Cell Death Differ. 25, 180–189 (2018).

    Article  PubMed  CAS  Google Scholar 

  159. Trichonas, G. et al. Receptor interacting protein kinases mediate retinal detachment-induced photoreceptor necrosis and compensate for inhibition of apoptosis. Proc. Natl. Acad. Sci. USA 107, 21695–21700 (2010).

  160. Koo, G. B. et al. Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics. Cell Res. 25, 707–725 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  161. Yang, C. et al. Regulation of RIP3 by the transcription factor Sp1 and the epigenetic regulator UHRF1 modulates cancer cell necroptosis. Cell Death Dis. 8, e3084 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  162. Nugues, A. L. et al. RIP3 is downregulated in human myeloid leukemia cells and modulates apoptosis and caspase-mediated p65/RelA cleavage. Cell Death Dis. 5, e1384 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  163. Feng, X. et al. Receptor-interacting protein kinase 3 is a predictor of survival and plays a tumor suppressive role in colorectal cancer. Neoplasma 62, 592–601 (2015).

    Article  PubMed  CAS  Google Scholar 

  164. Yang, H. et al. Contribution of RIP3 and MLKL to immunogenic cell death signaling in cancer chemotherapy. OncoImmunology 5, e1149673 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Vucur, M. et al. RIP3 inhibits inflammatory hepatocarcinogenesis but promotes cholestasis by controlling caspase-8- and JNK-dependent compensatory cell proliferation. Cell Rep. 4, 776–790 (2013).

  166. Höckendorf, U. et al. RIPK3 restricts myeloid leukemogenesis by promoting cell death and differentiation of leukemia initiating cells. Cancer Cell 30, 75–91 (2016).

    Article  PubMed  CAS  Google Scholar 

  167. Seifert, L. et al. The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression. Nature 532, 245–249 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  168. Xin, J. et al. Sensitizing acute myeloid leukemia cells to induced differentiation by inhibiting the RIP1/RIP3 pathway. Leukemia 31, 1154–1165 (2017).

    Article  PubMed  CAS  Google Scholar 

  169. Strilic, B. et al. Tumour-cell-induced endothelial cell necroptosis via death receptor 6 promotes metastasis. Nature 536, 215–218 (2016).

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

Supported by the National Basic Research (973) Program of China (2013CB910102), the National Natural Science Foundation of China (31471303 and 31671436), a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions and Fok Ying Tung Education Foundation for Young Teachers (151020) and the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2017NL31002,2017NL31004).

Author information

Authors and Affiliations

  1. Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medial College, Beijing; Suzhou Institute of Systems Medicine, Suzhou, Jiangsu, China

    Sudan He

  2. Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, Jiangsu, China

    Sudan He

  3. Key Laboratory of Stem Cells and Biomedical Materials of Jiangsu Province and Chinese Ministry of Science and Technology, Soochow University, Suzhou, Jiangsu, China

    Sudan He

  4. National Institute of Biological Sciences, Beijing, Zhongguancun Life Science Park, Beijing, China

    Xiaodong Wang

  5. Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China

    Xiaodong Wang

Authors
  1. Sudan He
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaodong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Sudan He or Xiaodong Wang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

He, S., Wang, X. RIP kinases as modulators of inflammation and immunity. Nat Immunol 19, 912–922 (2018). https://doi.org/10.1038/s41590-018-0188-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41590-018-0188-x

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing