1932

Abstract

The receptor-interacting protein kinase 1 (RIPK1) is recognized as a master upstream regulator that controls cell survival and inflammatory signaling as well as multiple cell death pathways, including apoptosis and necroptosis. The activation of RIPK1 kinase is extensively modulated by ubiquitination and phosphorylation, which are mediated by multiple factors that also control the activation of the NF-κB pathway. We discuss current findings regarding the genetic modulation of RIPK1 that controls its activation and interaction with downstream mediators, such as caspase-8 and RIPK3, to promote apoptosis and necroptosis. We also address genetic autoinflammatory human conditions that involve abnormal activation of RIPK1. Leveraging these new genetic and mechanistic insights, we postulate how an improved understanding of RIPK1 biology may support the development of therapeutics that target RIPK1 for the treatment of human inflammatory and neurodegenerative diseases.

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2021-11-23
2024-04-13
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Literature Cited

  1. 1. 
    Amin P, Florez M, Najafov A, Pan H, Geng J et al. 2018. Regulation of a distinct activated RIPK1 intermediate bridging complex I and complex II in TNFα-mediated apoptosis. PNAS 115:E5944–53
    [Google Scholar]
  2. 2. 
    Anderton H, Bandala-Sanchez E, Simpson DS, Rickard JA, Ng AP et al. 2019. RIPK1 prevents TRADD-driven, but TNFR1 independent, apoptosis during development. Cell Death Differ 26:877–89
    [Google Scholar]
  3. 3. 
    Asanomi Y, Shigemizu D, Miyashita A, Mitsumori R, Mori T et al. 2019. A rare functional variant of SHARPIN attenuates the inflammatory response and associates with increased risk of late-onset Alzheimer's disease. Mol. Med. 25:20
    [Google Scholar]
  4. 4. 
    Belshaw R, Pereira V, Katzourakis A, Talbot G, Paces J et al. 2004. Long-term reinfection of the human genome by endogenous retroviruses. PNAS 101:4894–99
    [Google Scholar]
  5. 5. 
    Berger SB, Kasparcova V, Hoffman S, Swift B, Dare L 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]
  6. 6. 
    Bertrand MJM, Milutinovic S, Dickson KM, Ho WC, Boudreault A 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]
  7. 7. 
    Boisson B, Laplantine E, Dobbs K, Cobat A, Tarantino N et al. 2015. Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia. J. Exp. Med. 212:939–51
    [Google Scholar]
  8. 8. 
    Boisson B, Laplantine E, Prando C, Giliani S, Israelsson E et al. 2012. Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency. Nat. Immunol. 13:1178–86
    [Google Scholar]
  9. 9. 
    Bowes J, Orozco G, Flynn E, Ho P, Brier R et al. 2011. Confirmation of TNIP1 and IL23A as susceptibility loci for psoriatic arthritis. Ann. Rheum. Dis. 70:1641–44
    [Google Scholar]
  10. 10. 
    Brennan FM, McInnes IB. 2008. Evidence that cytokines play a role in rheumatoid arthritis. J. Clin. Invest. 118:3537–45
    [Google Scholar]
  11. 11. 
    Caccamo A, Branca C, Piras IS, Ferreira E, Huentelman MJ et al. 2017. Necroptosis activation in Alzheimer's disease. Nat. Neurosci. 20:1236–46
    [Google Scholar]
  12. 12. 
    Camporez JP, Wang Y, Faarkrog K, Chukijrungroat N, Petersen KF, Shulman GI. 2017. Mechanism by which arylamine N-acetyltransferase 1 ablation causes insulin resistance in mice. PNAS 114:E11285–92
    [Google Scholar]
  13. 13. 
    Chen NJ, Chio II, Lin WJ, Duncan G, Chau H et al. 2008. Beyond tumor necrosis factor receptor: TRADD signaling in toll-like receptors. PNAS 105:12429–34
    [Google Scholar]
  14. 14. 
    Cho YS, Challa S, Moquin D, Genga R, Ray TD et al. 2009. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 137:1112–23
    [Google Scholar]
  15. 15. 
    Choi ME, Price DR, Ryter SW, Choi AMK. 2019. Necroptosis: a crucial pathogenic mediator of human disease. JCI Insight 4:e128834
    [Google Scholar]
  16. 16. 
    Chun HJ, Zheng L, Ahmad M, Wang J, Speirs CK et al. 2002. Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. Nature 419:395–99
    [Google Scholar]
  17. 17. 
    Cirulli ET, Lasseigne BN, Petrovski S, Sapp PC, Dion PA et al. 2015. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science 347:1436–41
    [Google Scholar]
  18. 18. 
    Cordier F, Grubisha O, Traincard F, Véron M, Delepierre M, Agou F 2009. The zinc finger of NEMO is a functional ubiquitin-binding domain. J. Biol. Chem. 284:2902–7
    [Google Scholar]
  19. 19. 
    Cuchet-Lourenço D, Eletto D, Wu C, Plagnol V, Papapietro O et al. 2018. Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation. Science 361:810–13
    [Google Scholar]
  20. 20. 
    Damgaard RB, Elliott PR, Swatek KN, Maher ER, Stepensky P et al. 2019. OTULIN deficiency in ORAS causes cell type-specific LUBAC degradation, dysregulated TNF signalling and cell death. EMBO Mol. Med. 11:e9324
    [Google Scholar]
  21. 21. 
    Damgaard RB, Walker JA, Marco-Casanova P, Morgan NV, Titheradge HL et al. 2016. The deubiquitinase OTULIN is an essential negative regulator of inflammation and autoimmunity. Cell 166:1215–30.e20
    [Google Scholar]
  22. 22. 
    Dannappel M, Vlantis K, Kumari S, Polykratis A, Kim C et al. 2014. RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis. Nature 513:90–94
    [Google Scholar]
  23. 23. 
    Degterev A, Hitomi J, Germscheid M, Ch'en IL, Korkina O et al. 2008. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat. Chem. Biol. 4:313–21
    [Google Scholar]
  24. 24. 
    Degterev A, Huang Z, Boyce M, Li Y, Jagtap P et al. 2005. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat. Chem. Biol. 1:112–19
    [Google Scholar]
  25. 25. 
    Delanghe T, Dondelinger Y, Bertrand MJM. 2020. RIPK1 kinase-dependent death: a symphony of phosphorylation events. Trends Cell Biol 30:189–200
    [Google Scholar]
  26. 26. 
    Dillon CP, Weinlich R, Rodriguez DA, Cripps JG, Quarato G et al. 2014. RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3. Cell 157:1189–202
    [Google Scholar]
  27. 27. 
    Dondelinger Y, Delanghe T, Priem D, Wynosky-Dolfi MA, Sorobetea D et al. 2019. Serine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation. Nat. Commun. 10:1729
    [Google Scholar]
  28. 28. 
    Dondelinger Y, Jouan-Lanhouet S, Divert T, Theatre E, Bertin J et al. 2015. NF-κB-independent role of IKKα/IKKβ in preventing RIPK1 kinase-dependent apoptotic and necroptotic cell death during TNF signaling. Mol. Cell 60:63–76
    [Google Scholar]
  29. 29. 
    Dowling JP, Alsabbagh M, Del Casale C, Liu ZG, Zhang J. 2019. TRADD regulates perinatal development and adulthood survival in mice lacking RIPK1 and RIPK3. Nat. Commun. 10:705
    [Google Scholar]
  30. 30. 
    Duprez L, Takahashi N, Van Hauwermeiren F, Vandendriessche B, Goossens V et al. 2011. RIP kinase-dependent necrosis drives lethal systemic inflammatory response syndrome. Immunity 35:908–18
    [Google Scholar]
  31. 31. 
    Dziedzic SA, Su Z, Barrett VJ, Najafov A, Mookhtiar AK et al. 2018. ABIN-1 regulates RIPK1 activation by linking Met1 ubiquitylation with Lys63 deubiquitylation in TNF-RSC. Nat. Cell Biol. 20:58–68
    [Google Scholar]
  32. 32. 
    Ea CK, Deng L, Xia ZP, Pineda G, Chen ZJ. 2006. Activation of IKK by TNFα requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO. Mol. Cell 22:245–57
    [Google Scholar]
  33. 33. 
    Ermolaeva MA, Michallet M-C, Papadopoulou N, Utermöhlen O, Kranidioti K et al. 2008. Function of TRADD in tumor necrosis factor receptor 1 signaling and in TRIF-dependent inflammatory responses. Nat. Immunol. 9:1037–46
    [Google Scholar]
  34. 34. 
    Freischmidt A, Müller K, Ludolph AC, Weishaupt JH, Andersen PM. 2017. Association of mutations in TBK1 with sporadic and familial amyotrophic lateral sclerosis and frontotemporal dementia. JAMA Neurol 74:110–13
    [Google Scholar]
  35. 35. 
    Fricker M, Vilalta A, Tolkovsky AM, Brown GC. 2013. Caspase inhibitors protect neurons by enabling selective necroptosis of inflamed microglia. J. Biol. Chem. 288:9145–52
    [Google Scholar]
  36. 36. 
    Garcia-Carbonell R, Wong J, Kim JY, Close LA, Boland BS et al. 2018. Elevated A20 promotes TNF-induced and RIPK1-dependent intestinal epithelial cell death. PNAS 115:E9192–200
    [Google Scholar]
  37. 37. 
    Gateva V, Sandling JK, Hom G, Taylor KE, Chung SA et al. 2009. A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat. Genet. 41:1228–33
    [Google Scholar]
  38. 38. 
    Gay NJ, Symmons MF, Gangloff M, Bryant CE 2014. Assembly and localization of Toll-like receptor signalling complexes. Nat. Rev. Immunol. 14:546–58
    [Google Scholar]
  39. 39. 
    Geng J, Ito Y, Shi L, Amin P, Chu J et al. 2017. Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis. Nat. Commun. 8:359
    [Google Scholar]
  40. 40. 
    Gerlach B, Cordier SM, Schmukle AC, Emmerich CH, Rieser E et al. 2011. Linear ubiquitination prevents inflammation and regulates immune signalling. Nature 471:591–96
    [Google Scholar]
  41. 41. 
    G'Sell RT, Gaffney PM, Powell DW 2015. A20-binding inhibitor of NF-κB Activation 1 is a physiologic inhibitor of NF-κB: a molecular switch for inflammation and autoimmunity. Arthritis Rheumatol 67:2292–302
    [Google Scholar]
  42. 42. 
    Guo WC, Lin GF, Zha YL, Lou KJ, Ma QW, Shen JH 2004. N-Acetyltransferase 2 gene polymorphism in a group of senile dementia patients in Shanghai suburb. Acta Pharmacol. Sin. 25:1112–17
    [Google Scholar]
  43. 43. 
    Guo X, Yin H, Chen Y, Li L, Li J, Liu Q 2016. TAK1 regulates caspase 8 activation and necroptotic signaling via multiple cell death checkpoints. Cell Death Dis 7:e2381
    [Google Scholar]
  44. 44. 
    Ha SC, Kim D, Hwang H-Y, Rich A, Kim Y-G, Kim KK. 2008. The crystal structure of the second Z-DNA binding domain of human DAI (ZBP1) in complex with Z-DNA reveals an unusual binding mode to Z-DNA. PNAS 105:20671–76
    [Google Scholar]
  45. 45. 
    Hall K, Cruz P, Tinoco I Jr., Jovin TM, van de Sande JH. 1984. ‘Z-RNA’–a left-handed RNA double helix. Nature 311:584–86
    [Google Scholar]
  46. 46. 
    Hanson EP, Monaco-Shawver L, Solt LA, Madge LA, Banerjee PP et al. 2008. Hypomorphic nuclear factor-κB essential modulator mutation database and reconstitution system identifies phenotypic and immunologic diversity. J. Allergy Clin. Immunol. 122:1169–77.e16
    [Google Scholar]
  47. 47. 
    Hayden MS, Ghosh S. 2012. NF-κB, the first quarter-century: remarkable progress and outstanding questions. Genes Dev 26:203–34
    [Google Scholar]
  48. 48. 
    He S, Liang Y, Shao F, Wang X. 2011. Toll-like receptors activate programmed necrosis in macrophages through a receptor-interacting kinase-3-mediated pathway. PNAS 108:20054–59
    [Google Scholar]
  49. 49. 
    He S, Wang L, Miao L, Wang T, Du F et al. 2009. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-α. Cell 137:1100–11
    [Google Scholar]
  50. 50. 
    He S, Wang X. 2018. RIP kinases as modulators of inflammation and immunity. Nat. Immunol. 19:912–22
    [Google Scholar]
  51. 51. 
    Heger K, Wickliffe KE, Ndoja A, Zhang J, Murthy A et al. 2018. OTULIN limits cell death and inflammation by deubiquitinating LUBAC. Nature 559:120–24
    [Google Scholar]
  52. 52. 
    Hsu H, Shu H-B, Pan M-G, Goeddel DV. 1996. TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell 84:299–308
    [Google Scholar]
  53. 53. 
    Hsu H, Xiong J, Goeddel DV. 1995. The TNF receptor 1-associated protein TRADD signals cell death and NF-κB activation. Cell 81:495–504
    [Google Scholar]
  54. 54. 
    Huang X, Tan S, Li Y, Cao S, Li X et al. 2021. Caspase inhibition prolongs inflammation by promoting a signaling complex with activated RIPK1. J. Cell Biol. 220:e202007127
    [Google Scholar]
  55. 55. 
    Ikeda F, Deribe YL, Skånland SS, Stieglitz B, Grabbe C et al. 2011. SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis. Nature 471:637–41
    [Google Scholar]
  56. 56. 
    Ingram JP, Thapa RJ, Fisher A, Tummers B, Zhang T et al. 2019. ZBP1/DAI drives RIPK3-mediated cell death induced by IFNs in the absence of RIPK1. J. Immunol. 203:1348–55
    [Google Scholar]
  57. 57. 
    Ito Y, Ofengeim D, Najafov A, Das S, Saberi S et al. 2016. RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS. Science 353:603–8
    [Google Scholar]
  58. 58. 
    Jiao H, Wachsmuth L, Kumari S, Schwarzer R, Lin J et al. 2020. Z-nucleic-acid sensing triggers ZBP1-dependent necroptosis and inflammation. Nature 580:391–95
    [Google Scholar]
  59. 59. 
    Kaiser WJ, Daley-Bauer LP, Thapa RJ, Mandal P, Berger SB et al. 2014. RIP1 suppresses innate immune necrotic as well as apoptotic cell death during mammalian parturition. PNAS 111:7753–58
    [Google Scholar]
  60. 60. 
    Kaiser WJ, Offermann MK. 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]
  61. 61. 
    Kaiser WJ, Sridharan H, Huang C, Mandal P, Upton JW et al. 2013. Toll-like receptor 3-mediated necrosis via TRIF, RIP3, and MLKL. J. Biol. Chem. 288:31268–79
    [Google Scholar]
  62. 62. 
    Kawasaki A, Ito S, Furukawa H, Hayashi T, Goto D et al. 2010. Association of TNFAIP3 interacting protein 1, TNIP1 with systemic lupus erythematosus in a Japanese population: A case-control association study. Arthritis Res. Ther. 12:R174
    [Google Scholar]
  63. 63. 
    Keusekotten K, Elliott PR, Glockner L, Fiil BK, Damgaard RB et al. 2013. OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-linked polyubiquitin. Cell 153:1312–26
    [Google Scholar]
  64. 64. 
    Knowles JW, Xie W, Zhang Z, Chennamsetty I, Assimes TL et al. 2015. Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene. J. Clin. Invest. 125:1739–51
    [Google Scholar]
  65. 65. 
    Koper MJ, Van Schoor E, Ospitalieri S, Vandenberghe R, Vandenbulcke M et al. 2020. Necrosome complex detected in granulovacuolar degeneration is associated with neuronal loss in Alzheimer's disease. Acta Neuropathol 139:463–84
    [Google Scholar]
  66. 66. 
    Kuriakose T, Man SM, Malireddi RKS, Karki R, Kesavardhana S et al. 2016. ZBP1/DAI is an innate sensor of influenza virus triggering the NLRP3 inflammasome and programmed cell death pathways. Sci. Immunol. 1:aag2045
    [Google Scholar]
  67. 67. 
    Lafont E, Draber P, Rieser E, Reichert M, Kupka S et al. 2018. TBK1 and IKKε prevent TNF-induced cell death by RIPK1 phosphorylation. Nat. Cell Biol. 20:1389–99
    [Google Scholar]
  68. 68. 
    Lalaoui N, Boyden SE, Oda H, Wood GM, Stone DL et al. 2020. Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease. Nature 577:103–8
    [Google Scholar]
  69. 69. 
    Laurien L, Nagata M, Schunke H, Delanghe T, Wiederstein JL et al. 2020. Autophosphorylation at serine 166 regulates RIP kinase 1-mediated cell death and inflammation. Nat. Commun. 11:1747
    [Google Scholar]
  70. 70. 
    Legarda-Addison D, Hase H, O'Donnell MA, Ting AT. 2009. NEMO/IKKγ regulates an early NF-κB-independent cell-death checkpoint during TNF signaling. Cell Death Differ 16:1279–88
    [Google Scholar]
  71. 71. 
    Lehle AS, Farin HF, Marquardt B, Michels BE, Magg T et al. 2019. Intestinal inflammation and dysregulated immunity in patients with inherited caspase-8 deficiency. Gastroenterology 156:275–78
    [Google Scholar]
  72. 72. 
    Li H, Kobayashi M, Blonska M, You Y, Lin X. 2006. Ubiquitination of RIP is required for tumor necrosis factor α-induced NF-κB activation. J. Biol. Chem. 281:13636–43
    [Google Scholar]
  73. 73. 
    Li J, McQuade T, Siemer AB, Napetschnig J, Moriwaki K et al. 2012. The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. Cell 150:339–50
    [Google Scholar]
  74. 74. 
    Li X, Zhang M, Huang X, Liang W, Li G et al. 2020. Ubiquitination of RIPK1 regulates its activation mediated by TNFR1 and TLRs signaling in distinct manners. Nat. Commun. 11:6364
    [Google Scholar]
  75. 75. 
    Li Y, Fuhrer M, Bahrami E, Socha P, Klaudel-Dreszler M et al. 2019. Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases. PNAS 116:970–75
    [Google Scholar]
  76. 76. 
    Lim J, Park H, Heisler J, Maculins T, Roose-Girma M et al. 2019. Autophagy regulates inflammatory programmed cell death via turnover of RHIM-domain proteins. eLife 8:e44452
    [Google Scholar]
  77. 77. 
    Lin J, Kumari S, Kim C, Van T-M, Wachsmuth L et al. 2016. RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation. Nature 540:124–28
    [Google Scholar]
  78. 78. 
    Lin Y, Devin A, Rodriguez Y, Liu ZG 1999. Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis. Genes Dev 13:2514–26
    [Google Scholar]
  79. 79. 
    Lindgren SW, Stojiljkovic I, Heffron F. 1996. Macrophage killing is an essential virulence mechanism of Salmonella typhimurium. PNAS 93:4197–201
    [Google Scholar]
  80. 80. 
    Maelfait J, Liverpool L, Bridgeman A, Ragan KB, Upton JW, Rehwinkel J 2017. Sensing of viral and endogenous RNA by ZBP1/DAI induces necroptosis. EMBO J 36:2529–43
    [Google Scholar]
  81. 81. 
    Makris C, Godfrey VL, Krähn-Senftleben G, Takahashi T, Roberts JL 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]
  82. 82. 
    Mandal P, Berger SB, Pillay S, Moriwaki K, Huang C et al. 2014. RIP3 induces apoptosis independent of pronecrotic kinase activity. Mol. Cell 56:481–95
    [Google Scholar]
  83. 83. 
    Maruyama H, Morino H, Ito H, Izumi Y, Kato H et al. 2010. Mutations of optineurin in amyotrophic lateral sclerosis. Nature 465:223–26
    [Google Scholar]
  84. 84. 
    Matsuzawa-Ishimoto Y, Shono Y, Gomez LE, Hubbard-Lucey VM, Cammer M et al. 2017. Autophagy protein ATG16L1 prevents necroptosis in the intestinal epithelium. J. Exp. Med. 214:3687–705
    [Google Scholar]
  85. 85. 
    Meinzer U, Barreau F, Esmiol-Welterlin S, Jung C, Villard C et al. 2012. Yersinia pseudotuberculosis effector YopJ subverts the Nod2/RICK/TAK1 pathway and activates caspase-1 to induce intestinal barrier dysfunction. Cell Host Microbe 11:337–51
    [Google Scholar]
  86. 86. 
    Meng H, Liu Z, Li X, Wang H, Jin T et al. 2018. Death-domain dimerization-mediated activation of RIPK1 controls necroptosis and RIPK1-dependent apoptosis. PNAS 115:E2001–9
    [Google Scholar]
  87. 87. 
    Micheau O, Lens S, Gaide O, Alevizopoulos K, Tschopp J 2001. NF-κB signals induce the expression of c-FLIP. Mol. Cell. Biol. 21:5299–305
    [Google Scholar]
  88. 88. 
    Micheau O, Tschopp J. 2003. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 114:181–90
    [Google Scholar]
  89. 89. 
    Mifflin L, Hu Z, Dufort C, Hession CC, Walker AJ et al. 2021. A RIPK1-regulated inflammatory microglial state in amyotrophic lateral sclerosis. PNAS 118:e2025102118
    [Google Scholar]
  90. 90. 
    Mompeán M, Li W, Li J, Laage S, Siemer AB et al. 2018. The structure of the necrosome RIPK1-RIPK3 core, a human hetero-amyloid signaling complex. Cell 173:1244–53.e10
    [Google Scholar]
  91. 91. 
    Moriwaki K, Chan FK. 2013. RIP3: a molecular switch for necrosis and inflammation. Genes Dev 27:1640–49
    [Google Scholar]
  92. 92. 
    Moulin M, Anderton H, Voss AK, Thomas T, Wong WW et al. 2012. IAPs limit activation of RIP kinases by TNF receptor 1 during development. EMBO J 31:1679–91
    [Google Scholar]
  93. 93. 
    Muendlein HI, Connolly WM, Magri Z, Smirnova I, Ilyukha V et al. 2021. ZBP1 promotes LPS-induced cell death and IL-1β release via RHIM-mediated interactions with RIPK1. Nat. Commun. 12:86
    [Google Scholar]
  94. 94. 
    Muendlein HI, Jetton D, Connolly WM, Eidell KP, Magri Z et al. 2020. cFLIPL protects macrophages from LPS-induced pyroptosis via inhibition of complex II formation. Science 367:1379–84
    [Google Scholar]
  95. 95. 
    Murthy A, Li Y, Peng I, Reichelt M, Katakam AK et al. 2014. A Crohn's disease variant in Atg16l1 enhances its degradation by caspase 3. Nature 506:456–62
    [Google Scholar]
  96. 96. 
    Musone SL, Taylor KE, Lu TT, Nititham J, Ferreira RC et al. 2008. Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus. Nat. Genet. 40:1062–64
    [Google Scholar]
  97. 97. 
    Nair RP, Duffin KC, Helms C, Ding J, Stuart PE et al. 2009. Genome-wide scan reveals association of psoriasis with IL-23 and NF-κB pathways. Nat. Genet. 41:199–204
    [Google Scholar]
  98. 98. 
    Najafov A, Luu HS, Mookhtiar AK, Mifflin L, Xia HG et al. 2021. RIPK1 promotes energy sensing by the mTORC1 pathway. Mol. Cell 81:370–85.e7
    [Google Scholar]
  99. 99. 
    Najjar M, Saleh D, Zelic M, Nogusa S, Shah S et al. 2016. RIPK1 and RIPK3 kinases promote cell-death-independent inflammation by Toll-like receptor 4. Immunity 45:46–59
    [Google Scholar]
  100. 100. 
    Newton K, Dugger DL, Maltzman A, Greve JM, Hedehus M et al. 2016. RIPK3 deficiency or catalyt-ically inactive RIPK1 provides greater benefit than MLKL deficiency in mouse models of inflammation and tissue injury. Cell Death Differ 23:1565–76
    [Google Scholar]
  101. 101. 
    Newton K, Dugger DL, Wickliffe KE, Kapoor N, de Almagro MC et al. 2014. Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosis. Science 343:1357–60
    [Google Scholar]
  102. 102. 
    Newton K, Wickliffe KE, Dugger DL, Maltzman A, Roose-Girma M et al. 2019. Cleavage of RIPK1 by caspase-8 is crucial for limiting apoptosis and necroptosis. Nature 574:428–31
    [Google Scholar]
  103. 103. 
    Newton K, Wickliffe KE, Maltzman A, Dugger DL, Reja R et al. 2019. Activity of caspase-8 determines plasticity between cell death pathways. Nature 575:679–82
    [Google Scholar]
  104. 104. 
    Newton K, Wickliffe KE, Maltzman A, Dugger DL, Strasser A et al. 2016. RIPK1 inhibits ZBP1-driven necroptosis during development. Nature 540:129–33
    [Google Scholar]
  105. 105. 
    Niccoli T, Partridge L, Isaacs AM. 2017. Ageing as a risk factor for ALS/FTD. Hum. Mol. Genet. 26:R105–13
    [Google Scholar]
  106. 106. 
    Nogusa S, Thapa RJ, Dillon CP, Liedmann S, Oguin TH3rd et al. 2016. RIPK3 activates parallel pathways of MLKL-driven necroptosis and FADD-mediated apoptosis to protect against influenza A virus. Cell Host Microbe 20:13–24
    [Google Scholar]
  107. 107. 
    Oakes JA, Davies MC, Collins MO. 2017. TBK1: a new player in ALS linking autophagy and neuroinflammation. Mol. Brain 10:5
    [Google Scholar]
  108. 108. 
    Oda H, Beck DB, Kuehn HS, Sampaio Moura N, Hoffmann P et al. 2019. Second case of HOIP deficiency expands clinical features and defines inflammatory transcriptome regulated by LUBAC. Front. Immunol. 10:479
    [Google Scholar]
  109. 109. 
    O'Donnell MA, Legarda-Addison D, Skountzos P, Yeh WC, Ting AT. 2007. Ubiquitination of RIP1 regulates an NF-κB-independent cell-death switch in TNF signaling. Curr. Biol. 17:418–24
    [Google Scholar]
  110. 110. 
    Ofengeim D, Ito Y, Najafov A, Zhang Y, Shan B et al. 2015. Activation of necroptosis in multiple sclerosis. Cell Rep 10:1836–49
    [Google Scholar]
  111. 111. 
    Ofengeim D, Mazzitelli S, Ito Y, DeWitt JP, Mifflin L et al. 2017. RIPK1 mediates a disease-associated microglial response in Alzheimer's disease. PNAS 114:E8788–97
    [Google Scholar]
  112. 112. 
    Ofengeim D, Yuan J. 2013. Regulation of RIP1 kinase signalling at the crossroads of inflammation and cell death. Nat. Rev. Mol. Cell Biol. 14:727–36
    [Google Scholar]
  113. 113. 
    Ogawa M. 1999.. [ Biochemical, molecular genetic and ecogenetic studies of polymorphic arylamine N-acetyltransferase (NAT2) in the brain. ]. Fukuoka Igaku Zasshi 90:118–31 In Japanese with English abstract )
    [Google Scholar]
  114. 114. 
    Onizawa M, Oshima S, Schulze-Topphoff U, Oses-Prieto JA, Lu T et al. 2015. The ubiquitin-modifying enzyme A20 restricts ubiquitination of the kinase RIPK3 and protects cells from necroptosis. Nat. Immunol. 16:618–27
    [Google Scholar]
  115. 115. 
    Orning P, Weng D, Starheim K, Ratner D, Best Z et al. 2018. Pathogen blockade of TAK1 triggers caspase-8-dependent cleavage of gasdermin D and cell death. Science 362:1064–69
    [Google Scholar]
  116. 116. 
    Panayotova-Dimitrova D, Feoktistova M, Ploesser M, Kellert B, Hupe M et al. 2013. cFLIP regulates skin homeostasis and protects against TNF-induced keratinocyte apoptosis. Cell Rep 5:397–408
    [Google Scholar]
  117. 117. 
    Park HH, Lo Y-C, Lin S-C, Wang L, Yang JK, Wu H 2007. The death domain superfamily in intracellular signaling of apoptosis and inflammation. Annu. Rev. Immunol. 25:561–86
    [Google Scholar]
  118. 118. 
    Park Y-H, Jeong MS, Park HH, Jang SB. 2013. Formation of the death domain complex between FADD and RIP1 proteins in vitro. Biochim. Biophys. Acta Proteins Proteom. 1834:292–300
    [Google Scholar]
  119. 119. 
    Patel S, Webster JD, Varfolomeev E, Kwon YC, Cheng JH et al. 2020. RIP1 inhibition blocks inflammatory diseases but not tumor growth or metastases. Cell Death Differ 27:161–75
    [Google Scholar]
  120. 120. 
    Peltzer N, Rieser E, Taraborrelli L, Draber P, Darding M et al. 2014. HOIP deficiency causes embryonic lethality by aberrant TNFR1-mediated endothelial cell death. Cell Rep 9:153–65
    [Google Scholar]
  121. 121. 
    Placido D, Brown BA2nd, Lowenhaupt K, Rich A, Athanasiadis A 2007. A left-handed RNA double helix bound by the Zα domain of the RNA-editing enzyme ADAR1. Structure 15:395–404
    [Google Scholar]
  122. 122. 
    Plenge RM, Cotsapas C, Davies L, Price AL, de Bakker PI et al. 2007. Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nat. Genet. 39:1477–82
    [Google Scholar]
  123. 123. 
    Pobezinskaya YL, Kim YS, Choksi S, Morgan MJ, Li T et al. 2008. The function of TRADD in signaling through tumor necrosis factor receptor 1 and TRIF-dependent Toll-like receptors. Nat. Immunol. 9:1047–54
    [Google Scholar]
  124. 124. 
    Polykratis A, Hermance N, Zelic M, Roderick J, Kim C et al. 2014. Cutting edge: RIPK1 Kinase inactive mice are viable and protected from TNF-induced necroptosis in vivo. J. Immunol. 193:1539–43
    [Google Scholar]
  125. 125. 
    Rebsamen M, Heinz LX, Meylan E, Michallet MC, Schroder K et al. 2009. DAI/ZBP1 recruits RIP1 and RIP3 through RIP homotypic interaction motifs to activate NF-κB. EMBO Rep 10:916–22
    [Google Scholar]
  126. 126. 
    Rickard JA, O'Donnell JA, Evans JM, Lalaoui N, Poh AR et al. 2014. RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis. Cell 157:1175–88
    [Google Scholar]
  127. 127. 
    Robinson N, McComb S, Mulligan R, Dudani R, Krishnan L, Sad S. 2012. Type I interferon induces necroptosis in macrophages during infection with Salmonella enterica serovar Typhimurium. Nat. Immunol. 13:954–62
    [Google Scholar]
  128. 128. 
    Rocha L, Garcia C, de Mendonca A, Gil JP, Bishop DT, Lechner MC. 1999. N-acetyltransferase (NAT2) genotype and susceptibility of sporadic Alzheimer's disease. Pharmacogenetics 9:9–15
    [Google Scholar]
  129. 129. 
    Rothe M, Pan MG, Henzel WJ, Ayres TM, Goeddel DV. 1995. The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins. Cell 83:1243–52
    [Google Scholar]
  130. 130. 
    Schmidt-Supprian M, Bloch W, Courtois G, Addicks K, Israel A et al. 2000. NEMO/IKKγ-deficient mice model incontinentia pigmenti. Mol. Cell 5:981–92
    [Google Scholar]
  131. 131. 
    Schwartz T, Behlke J, Lowenhaupt K, Heinemann U, Rich A 2001. Structure of the DLM-1-Z-DNA complex reveals a conserved family of Z-DNA-binding proteins. Nat. Struct. Biol. 8:761–65
    [Google Scholar]
  132. 132. 
    Seo J, Lee EW, Sung H, Seong D, Dondelinger Y et al. 2016. CHIP controls necroptosis through ubiquitylation- and lysosome-dependent degradation of RIPK3. Nat. Cell Biol. 18:291–302
    [Google Scholar]
  133. 133. 
    Shan B, Pan H, Najafov A, Yuan J 2018. Necroptosis in development and diseases. Genes Dev 32:327–40
    [Google Scholar]
  134. 134. 
    Shigemura T, Kaneko N, Kobayashi N, Kobayashi K, Takeuchi Y et al. 2016. Novel heterozygous C243Y A20/TNFAIP3 gene mutation is responsible for chronic inflammation in autosomal-dominant Behçet's disease. RMD Open 2:e000223
    [Google Scholar]
  135. 135. 
    Shu HB, Takeuchi M, Goeddel DV. 1996. The tumor necrosis factor receptor 2 signal transducers TRAF2 and c-IAP1 are components of the tumor necrosis factor receptor 1 signaling complex. PNAS 93:13973–78
    [Google Scholar]
  136. 136. 
    Smahi A, Courtois G, Vabres P, Yamaoka S, Heuertz S et al.Int. Incontinentia Pigment. Consort 2000. Genomic rearrangement in NEMO impairs NF-κB activation and is a cause of incontinentia pigmenti. Nature 405:466–72
    [Google Scholar]
  137. 137. 
    Stanger BZ, Leder P, Lee TH, Kim E, Seed B 1995. RIP: a novel protein containing a death domain that interacts with Fas/APO-1 (CD95) in yeast and causes cell death. Cell 81:513–23
    [Google Scholar]
  138. 138. 
    Stappenbeck TS, Rioux JD, Mizoguchi A, Saitoh T, Huett A et al. 2011. Crohn disease: a current perspective on genetics, autophagy and immunity. Autophagy 7:355–74
    [Google Scholar]
  139. 139. 
    Su Z, Dziedzic SA, Hu D, Barrett VJ, Broekema N et al. 2019. ABIN-1 heterozygosity sensitizes to innate immune response in both RIPK1-dependent and RIPK1-independent manner. Cell Death Differ 26:1077–88
    [Google Scholar]
  140. 140. 
    Sun L, Wang H, Wang Z, He S, Chen S et al. 2012. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell 148:213–27
    [Google Scholar]
  141. 141. 
    Sun X, Lee J, Navas T, Baldwin DT, Stewart TA, Dixit VM 1999. RIP3, a novel apoptosis-inducing kinase. J. Biol. Chem. 274:16871–75
    [Google Scholar]
  142. 142. 
    Sun X, Yin J, Starovasnik MA, Fairbrother WJ, Dixit VM. 2002. Identification of a novel homotypic interaction motif required for the phosphorylation of receptor-interacting protein (RIP) by RIP3. J. Biol. Chem. 277:9505–11
    [Google Scholar]
  143. 143. 
    Taft J, Markson M, Legarda D, Patel R, Chan M et al. 2021. Human TBK1 deficiency leads to autoinflammation driven by TNF-induced cell death. Cell 184:444763.e20
    [Google Scholar]
  144. 144. 
    Takahashi N, Vereecke L, Bertrand MJ, Duprez L, Berger SB et al. 2014. RIPK1 ensures intestinal homeostasis by protecting the epithelium against apoptosis. Nature 513:95–99
    [Google Scholar]
  145. 145. 
    Takaoka A, Wang Z, Choi MK, Yanai H, Negishi H et al. 2007. DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature 448:501–5
    [Google Scholar]
  146. 146. 
    Tang Y, Tu H, Zhang J, Zhao X, Wang Y et al. 2019. K63-linked ubiquitination regulates RIPK1 kinase activity to prevent cell death during embryogenesis and inflammation. Nat. Commun. 10:4157
    [Google Scholar]
  147. 147. 
    Tao P, Sun J, Wu Z, Wang S, Wang J et al. 2020. A dominant autoinflammatory disease caused by non-cleavable variants of RIPK1. Nature 577:109–14
    [Google Scholar]
  148. 148. 
    Thapa RJ, Ingram JP, Ragan KB, Nogusa S, Boyd DF et al. 2016. DAI senses influenza A virus genomic RNA and activates RIPK3-dependent cell death. Cell Host Microbe 20:674–81
    [Google Scholar]
  149. 149. 
    Thapa RJ, Nogusa S, Chen P, Maki JL, Lerro A et al. 2013. Interferon-induced RIP1/RIP3-mediated necrosis requires PKR and is licensed by FADD and caspases. PNAS 110:E3109–18
    [Google Scholar]
  150. 150. 
    Ting AT, Bertrand MJM. 2016. More to life than NF-κB in TNFR1 Signaling. Trends Immunol 37:535–45
    [Google Scholar]
  151. 151. 
    Tokunaga F, Nakagawa T, Nakahara M, Saeki Y, Taniguchi M et al. 2011. SHARPIN is a component of the NF-κB-activating linear ubiquitin chain assembly complex. Nature 471:633–36
    [Google Scholar]
  152. 152. 
    Tokunaga F, Sakata S, Saeki Y, Satomi Y, Kirisako T et al. 2009. Involvement of linear polyubiquitylation of NEMO in NF-κB activation. Nat. Cell Biol. 11:123–32
    [Google Scholar]
  153. 153. 
    Tummers B, Green DR. 2017. Caspase-8: regulating life and death. Immunol. Rev. 277:76–89
    [Google Scholar]
  154. 154. 
    Uchiyama Y, Kim CA, Pastorino AC, Ceroni J, Lima PP et al. 2019. Primary immunodeficiency with chronic enteropathy and developmental delay in a boy arising from a novel homozygous RIPK1 variant. J. Hum. Genet. 64:955–60
    [Google Scholar]
  155. 155. 
    Upton JW, Kaiser WJ, Mocarski ES. 2008. Cytomegalovirus M45 cell death suppression requires receptor-interacting protein (RIP) homotypic interaction motif (RHIM)-dependent interaction with RIP1. J. Biol. Chem. 283:16966–70
    [Google Scholar]
  156. 156. 
    Upton JW, Kaiser WJ, Mocarski ES. 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]
  157. 157. 
    Vlantis K, Wullaert A, Polykratis A, Kondylis V, Dannappel M et al. 2016. NEMO prevents RIP kinase 1-mediated epithelial cell death and chronic intestinal inflammation by NF-κB-dependent and -independent functions. Immunity 44:553–67
    [Google Scholar]
  158. 158. 
    Wang AH, Quigley GJ, Kolpak FJ, Crawford JL, van Boom JH et al. 1979. Molecular structure of a left-handed double helical DNA fragment at atomic resolution. Nature 282:680–86
    [Google Scholar]
  159. 159. 
    Wang H, Sun L, Su L, Rizo J, Liu L 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]
  160. 160. 
    Wang L, Du F, Wang X 2008. TNF-α induces two distinct caspase-8 activation pathways. Cell 133:693–703
    [Google Scholar]
  161. 161. 
    Wang R, Li H, Wu J, Cai ZY, Li B et al. 2020. Gut stem cell necroptosis by genome instability triggers bowel inflammation. Nature 580:386–90
    [Google Scholar]
  162. 162. 
    Webster JD, Kwon YC, Park S, Zhang H, Corr N et al. 2020. RIP1 kinase activity is critical for skin inflammation but not for viral propagation. J. Leukoc. Biol. 107:941–52
    [Google Scholar]
  163. 163. 
    Wellcome Trust Case Control Consort 2007. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447:661–78
    [Google Scholar]
  164. 164. 
    Xu D, Jin T, Zhu H, Chen H, Ofengeim D et al. 2018. TBK1 suppresses RIPK1-driven apoptosis and inflammation during development and in aging. Cell 174:1477–91.e19
    [Google Scholar]
  165. 165. 
    Xu D, Zhao H, Jin M, Zhu H, Shan B et al. 2020. Modulating TRADD to restore cellular homeostasis and inhibit apoptosis. Nature 587:133–38
    [Google Scholar]
  166. 166. 
    Yang D, Liang Y, Zhao S, Ding Y, Zhuang Q et al. 2020. ZBP1 mediates interferon-induced necroptosis. Cell. Mol. Immunol. 17:356–68
    [Google Scholar]
  167. 167. 
    Yuan J, Amin P, Ofengeim D. 2019. Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases. Nat. Rev. Neurosci. 20:19–33
    [Google Scholar]
  168. 168. 
    Zhang D, Lin J, Han J 2010. Receptor-interacting protein (RIP) kinase family. Cell. Mol. Immunol. 7:243–49
    [Google Scholar]
  169. 169. 
    Zhang D-M, Cheng L-Q, Zhai Z-F, Feng L, Zhong B-Y et al. 2013. Single-nucleotide polymorphism and haplotypes of TNIP1 associated with systemic lupus erythematosus in a Chinese Han population. J. Rheumatol. 40:1535–44
    [Google Scholar]
  170. 170. 
    Zhang DW, Shao J, Lin J, Zhang N, Lu BJ et al. 2009. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 325:332–36
    [Google Scholar]
  171. 171. 
    Zhang T, Yin C, Boyd DF, Quarato G, Ingram JP et al. 2020. Influenza virus Z-RNAs induce ZBP1-mediated necroptosis. Cell 180:1115–29.e13
    [Google Scholar]
  172. 172. 
    Zhang X, Dowling JP, Zhang J. 2019. RIPK1 can mediate apoptosis in addition to necroptosis during embryonic development. Cell Death Dis 10:245
    [Google Scholar]
  173. 173. 
    Zhang X, Zhang H, Xu C, Li X, Li M et al. 2019. Ubiquitination of RIPK1 suppresses programmed cell death by regulating RIPK1 kinase activation during embryogenesis. Nat. Commun. 10:4158
    [Google Scholar]
  174. 174. 
    Zhao J, Jitkaew S, Cai Z, Choksi S, Li Q 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]
  175. 175. 
    Zheng C, Huang Y, Ye Z, Wang Y, Tang Z et al. 2018. Infantile onset intractable inflammatory bowel disease due to novel heterozygous mutations in TNFAIP3 (A20). Inflamm. Bowel Dis. 24:2613–20
    [Google Scholar]
  176. 176. 
    Zhou Q, Snipas S, Orth K, Muzio M, Dixit VM, Salvesen GS. 1997. Target protease specificity of the viral serpin CrmA: analysis of five caspases. J. Biol. Chem. 272:7797–800
    [Google Scholar]
  177. 177. 
    Zhou Q, Wang H, Schwartz DM, Stoffels M, Park YH et al. 2016. Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease. Nat. Genet. 48:67–73
    [Google Scholar]
  178. 178. 
    Zhou Q, Yu X, Demirkaya E, Deuitch N, Stone D et al. 2016. Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease. PNAS 113:10127–32
    [Google Scholar]
  179. 179. 
    Zhu G, Wu C-J, Zhao Y, Ashwell JD. 2007. Optineurin negatively regulates TNFα- induced NF-κB activation by competing with NEMO for ubiquitinated RIP. Curr. Biol. 17:1438–43
    [Google Scholar]
  180. 180. 
    Zilberman-Rudenko J, Shawver LM, Wessel AW, Luo Y, Pelletier M et al. 2016. Recruitment of A20 by the C-terminal domain of NEMO suppresses NF-κB activation and autoinflammatory disease. PNAS 113:1612–17
    [Google Scholar]
  181. 181. 
    Zou C, Mifflin L, Hu Z, Zhang T, Shan B et al. 2020. Reduction of mNAT1/hNAT2 contributes to cerebral endothelial necroptosis and Aβ accumulation in Alzheimer's disease. Cell Rep 33:108447
    [Google Scholar]
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