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Abstract

Apoptosis, necroptosis, and pyroptosis are genetically programmed cell death mechanisms that eliminate obsolete, damaged, infected, and self-reactive cells. Apoptosis fragments cells in a manner that limits immune cell activation, whereas the lytic death programs of necroptosis and pyroptosis release proinflammatory intracellular contents. Apoptosis fine-tunes tissue architecture during mammalian development, promotes tissue homeostasis, and is crucial for averting cancer and autoimmunity. All three cell death mechanisms are deployed to thwart the spread of pathogens. Disabling regulators of cell death signaling in mice has revealed how excessive cell death can fuel acute or chronic inflammation. Here we review strategies for modulating cell death in the context of disease. For example, BCL-2 inhibitor venetoclax, an inducer of apoptosis, is approved for the treatment of certain hematologic malignancies. By contrast, inhibition of RIPK1, NLRP3, GSDMD, or NINJ1 to limit proinflammatory cell death and/or the release of large proinflammatory molecules from dying cells may benefit patients with inflammatory diseases.

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2024-01-24
2024-05-07
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Literature Cited

  1. 1.
    Stockwell BR. 2022. Ferroptosis turns 10: emerging mechanisms, physiological functions, and therapeutic applications. Cell 185:240121
    [Google Scholar]
  2. 2.
    Adams JM, Cory S. 2018. The BCL-2 arbiters of apoptosis and their growing role as cancer targets. Cell Death Differ. 25:2736
    [Google Scholar]
  3. 3.
    Jost PJ, Vucic D. 2020. Regulation of cell death and immunity by XIAP. Cold Spring Harb. Perspect. Biol. 12:a036426
    [Google Scholar]
  4. 4.
    Kerr JF, Wyllie AH, Currie AR. 1972. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26:23957
    [Google Scholar]
  5. 5.
    Ning X, Wang Y, Jing M, Sha M, Lv M et al. 2019. Apoptotic caspases suppress type I interferon production via the cleavage of cGAS, MAVS, and IRF3. Mol. Cell 74:1931.e7
    [Google Scholar]
  6. 6.
    Nagata S. 2018. Apoptosis and clearance of apoptotic cells. Annu. Rev. Immunol. 36:489517
    [Google Scholar]
  7. 7.
    Lindsten T, Ross AJ, King A, Zong WX, Rathmell JC et al. 2000. The combined functions of proapo-ptotic Bcl-2 family members Bak and Bax are essential for normal development of multiple tissues. Mol. Cell 6:138999
    [Google Scholar]
  8. 8.
    Ke FFS, Vanyai HK, Cowan AD, Delbridge ARD, Whitehead L et al. 2018. Embryogenesis and adult life in the absence of intrinsic apoptosis effectors BAX, BAK, and BOK. Cell 173:121730.e17
    [Google Scholar]
  9. 9.
    Ke FS, Holloway S, Uren RT, Wong AW, Little MH et al. 2022. The BCL-2 family member BID plays a role during embryonic development in addition to its BH3-only protein function by acting in parallel to BAX, BAK and BOK. EMBO J. 41:e110300
    [Google Scholar]
  10. 10.
    Llambi F, Wang YM, Victor B, Yang M, Schneider DM et al. 2016. BOK is a non-canonical BCL-2 family effector of apoptosis regulated by ER-associated degradation. Cell 165:42133
    [Google Scholar]
  11. 11.
    Flores-Romero H, Hohorst L, John M, Albert MC, King LE et al. 2022. BCL-2-family protein tBID can act as a BAX-like effector of apoptosis. EMBO J 41:e108690
    [Google Scholar]
  12. 12.
    Sarosiek KA, Fraser C, Muthalagu N, Bhola PD, Chang W et al. 2017. Developmental regulation of mitochondrial apoptosis by c-Myc governs age- and tissue-specific sensitivity to cancer therapeutics. Cancer Cell 31:14256
    [Google Scholar]
  13. 13.
    Akasaka T, Kishimori C, Fukutsuka K, Nakagawa M, Takeoka K et al. 2017. The novel double-hit, t(8;22)(q24;q11)/MYC-IGL and t(14;15)(q32;q24)/IGH-BCL2A1, in diffuse large B-cell lymphoma. Cancer Genet 214/215:2631
    [Google Scholar]
  14. 14.
    Haq R, Yokoyama S, Hawryluk EB, Jonsson GB, Frederick DT et al. 2013. BCL2A1 is a lineage-specific antiapoptotic melanoma oncogene that confers resistance to BRAF inhibition. PNAS 110:432126
    [Google Scholar]
  15. 15.
    Newton K, Gitlin AD. 2022. Deubiquitinases in cell death and inflammation. Biochem. J. 479:110319
    [Google Scholar]
  16. 16.
    Roberts AW, Wei AH, Huang DCS. 2021. BCL2 and MCL1 inhibitors for hematologic malignancies. Blood 138:112036
    [Google Scholar]
  17. 17.
    Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND et al. 2013. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat. Med. 19:2028
    [Google Scholar]
  18. 18.
    Esteve-Arenys A, Valero JG, Chamorro-Jorganes A, Gonzalez D, Rodriguez V et al. 2018. The BET bromodomain inhibitor CPI203 overcomes resistance to ABT-199 (venetoclax) by downregulation of BFL-1/A1 in in vitro and in vivo models of MYC+/BCL2+ double hit lymphoma. Oncogene 37:183044
    [Google Scholar]
  19. 19.
    Deng Y, Diepstraten ST, Potts MA, Giner G, Trezise S et al. 2022. Generation of a CRISPR activation mouse that enables modelling of aggressive lymphoma and interrogation of venetoclax resistance. Nat. Commun. 13:4739
    [Google Scholar]
  20. 20.
    Stutz MD, Allison CC, Ojaimi S, Preston SP, Doerflinger M et al. 2021. Macrophage and neutrophil death programs differentially confer resistance to tuberculosis. Immunity 54:175871.e7
    [Google Scholar]
  21. 21.
    Kvansakul M, Hinds MG. 2013. Structural biology of the Bcl-2 family and its mimicry by viral proteins. Cell Death Dis 4:e909
    [Google Scholar]
  22. 22.
    Fitzsimmons L, Cartlidge R, Chang C, Sejic N, Galbraith LCA et al. 2020. EBV BCL-2 homologue BHRF1 drives chemoresistance and lymphomagenesis by inhibiting multiple cellular pro-apoptotic proteins. Cell Death Differ 27:155468
    [Google Scholar]
  23. 23.
    Pan R, Ryan J, Pan D, Wucherpfennig KW, Letai A. 2022. Augmenting NK cell–based immunotherapy by targeting mitochondrial apoptosis. Cell 185:152138.e18
    [Google Scholar]
  24. 24.
    Nozaki K, Maltez VI, Rayamajhi M, Tubbs AL, Mitchell JE et al. 2022. Caspase-7 activates ASM to repair gasdermin and perforin pores. Nature 606:96067
    [Google Scholar]
  25. 25.
    Weant AE, Michalek RD, Khan IU, Holbrook BC, Willingham MC, Grayson JM. 2008. Apoptosis regulators Bim and Fas function concurrently to control autoimmunity and CD8+ T cell contraction. Immunity 28:21830
    [Google Scholar]
  26. 26.
    Hughes PD, Belz GT, Fortner KA, Budd RC, Strasser A, Bouillet P. 2008. Apoptosis regulators Fas and Bim cooperate in shutdown of chronic immune responses and prevention of autoimmunity. Immunity 28:197205
    [Google Scholar]
  27. 27.
    Newton K, Dixit VM, Kayagaki N. 2021. Dying cells fan the flames of inflammation. Science 374:107680
    [Google Scholar]
  28. 28.
    Estornes Y, Toscano F, Virard F, Jacquemin G, Pierrot A et al. 2012. dsRNA induces apoptosis through an atypical death complex associating TLR3 to caspase-8. Cell Death Differ 19:148294
    [Google Scholar]
  29. 29.
    Zinngrebe J, Rieser E, Taraborrelli L, Peltzer N, Hartwig T et al. 2016. LUBAC deficiency perturbs TLR3 signaling to cause immunodeficiency and autoinflammation. J. Exp. Med. 213:267189
    [Google Scholar]
  30. 30.
    Daley-Bauer LP, Roback L, Crosby LN, McCormick AL, Feng Y et al. 2017. Mouse cytomegalovirus M36 and M45 death suppressors cooperate to prevent inflammation resulting from antiviral programmed cell death pathways. PNAS 114:E278695
    [Google Scholar]
  31. 31.
    Guo H, Omoto S, Harris PA, Finger JN, Bertin J et al. 2015. Herpes simplex virus suppresses necroptosis in human cells. Cell Host Microbe 17:24351
    [Google Scholar]
  32. 32.
    Petrie EJ, Sandow JJ, Lehmann WIL, Liang LY, Coursier D et al. 2019. Viral MLKL homologs subvert necroptotic cell death by sequestering cellular RIPK3. Cell Rep 28:330919.e5
    [Google Scholar]
  33. 33.
    Zhang T, Yin C, Boyd DF, Quarato G, Ingram JP et al. 2020. Influenza virus Z-RNAs induce ZBP1-mediated necroptosis. Cell 180:111529.e13
    [Google Scholar]
  34. 34.
    Wang R, Li H, Wu J, Cai ZY, Li B et al. 2020. Gut stem cell necroptosis by genome instability triggers bowel inflammation. Nature 580:38690
    [Google Scholar]
  35. 35.
    Jiao H, Wachsmuth L, Kumari S, Schwarzer R, Lin J et al. 2020. Z-nucleic-acid sensing triggers ZBP1-dependent necroptosis and inflammation. Nature 580:39195
    [Google Scholar]
  36. 36.
    Fu TM, Li Y, Lu A, Li Z, Vajjhala PR et al. 2016. Cryo-EM structure of caspase-8 tandem DED filament reveals assembly and regulation mechanisms of the death-inducing signaling complex. Mol. Cell 64:23650
    [Google Scholar]
  37. 37.
    Fox JL, Hughes MA, Meng X, Sarnowska NA, Powley IR et al. 2021. Cryo-EM structural analysis of FADD:caspase-8 complexes defines the catalytic dimer architecture for co-ordinated control of cell fate. Nat. Commun. 12:819
    [Google Scholar]
  38. 38.
    Boatright KM, Deis C, Denault JB, Sutherlin DP, Salvesen GS. 2004. Activation of caspases-8 and -10 by FLIPL. Biochem. J. 382:65157
    [Google Scholar]
  39. 39.
    Yu JW, Jeffrey PD, Shi Y. 2009. Mechanism of procaspase-8 activation by c-FLIPL. PNAS 106:816974
    [Google Scholar]
  40. 40.
    Keller N, Mares J, Zerbe O, Grutter MG. 2009. Structural and biochemical studies on procaspase-8: new insights on initiator caspase activation. Structure 17:43848
    [Google Scholar]
  41. 41.
    Humphreys LM, Fox JP, Higgins CA, Majkut J, Sessler T et al. 2020. A revised model of TRAIL-R2 DISC assembly explains how FLIPL can inhibit or promote apoptosis. EMBO Rep 21:e49254
    [Google Scholar]
  42. 42.
    Hughes MA, Powley IR, Jukes-Jones R, Horn S, Feoktistova M et al. 2016. Co-operative and hierarchical binding of c-FLIP and caspase-8: A unified model defines how c-FLIP isoforms differentially control cell fate. Mol. Cell 61:83449
    [Google Scholar]
  43. 43.
    Tanzer MC, Khan N, Rickard JA, Etemadi N, Lalaoui N et al. 2017. Combination of IAP antagonist and IFNγ activates novel caspase-10- and RIPK1-dependent cell death pathways. Cell Death Differ 24:48191
    [Google Scholar]
  44. 44.
    Horn S, Hughes MA, Schilling R, Sticht C, Tenev T et al. 2017. Caspase-10 negatively regulates caspase-8-mediated cell death, switching the response to CD95L in favor of NF-κB activation and cell survival. Cell Rep. 19:78597
    [Google Scholar]
  45. 45.
    Varfolomeev E, Maecker H, Sharp D, Lawrence D, Renz M et al. 2005. Molecular determinants of kinase pathway activation by Apo2 ligand/tumor necrosis factor–related apoptosis-inducing ligand. J. Biol. Chem. 280:40599608
    [Google Scholar]
  46. 46.
    Henry CM, Martin SJ. 2017. Caspase-8 acts in a non-enzymatic role as a scaffold for assembly of a pro-inflammatory “FADDosome” complex upon TRAIL stimulation. Mol. Cell 65:71529.e5
    [Google Scholar]
  47. 47.
    Hartwig T, Montinaro A, von Karstedt S, Sevko A, Surinova S et al. 2017. The TRAIL-induced cancer secretome promotes a tumor-supportive immune microenvironment via CCR2. Mol. Cell 65:73042.e5
    [Google Scholar]
  48. 48.
    Kreuz S, Siegmund D, Rumpf JJ, Samel D, Leverkus M et al. 2004. NFκB activation by Fas is mediated through FADD, caspase-8, and RIP and is inhibited by FLIP. J. Cell Biol. 166:36980
    [Google Scholar]
  49. 49.
    Tummers B, Mari L, Guy CS, Heckmann BL, Rodriguez DA et al. 2020. Caspase-8-dependent inflammatory responses are controlled by its adaptor, FADD, and necroptosis. Immunity 52:9941006.e8
    [Google Scholar]
  50. 50.
    Newton K. 2020. Multitasking kinase RIPK1 regulates cell death and inflammation. Cold Spring Harb. Perspect. Biol. 12:a036368
    [Google Scholar]
  51. 51.
    Murphy JM. 2020. The killer pseudokinase mixed lineage kinase domain-like protein (MLKL). Cold Spring Harb. Perspect. Biol. 12:a036376
    [Google Scholar]
  52. 52.
    Schuster IS, Sng XYX, Lau CM, Powell DR, Weizman OE et al. 2023. Infection induces tissue-resident memory NK cells that safeguard tissue health. Immunity 56:53146.e6
    [Google Scholar]
  53. 53.
    Butt D, Chan TD, Bourne K, Hermes JR, Nguyen A et al. 2015. FAS inactivation releases unconventional germinal center B cells that escape antigen control and drive IgE and autoantibody production. Immunity 42:890902
    [Google Scholar]
  54. 54.
    Maccari ME, Fuchs S, Kury P, Andrieux G, Volkl S et al. 2021. A distinct CD38+CD45RA+ population of CD4+, CD8+, and double-negative T cells is controlled by FAS. J. Exp. Med. 218:e20192191
    [Google Scholar]
  55. 55.
    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 574:42831
    [Google Scholar]
  56. 56.
    Lalaoui N, Boyden SE, Oda H, Wood GM, Stone DL et al. 2020. Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease. Nature 577:1038
    [Google Scholar]
  57. 57.
    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 577:10914
    [Google Scholar]
  58. 58.
    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 419:39599
    [Google Scholar]
  59. 59.
    Bolze A, Byun M, McDonald D, Morgan NV, Abhyankar A et al. 2010. Whole-exome-sequencing-based discovery of human FADD deficiency. Am. J. Hum. Genet. 87:87381
    [Google Scholar]
  60. 60.
    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 156:27578
    [Google Scholar]
  61. 61.
    Gitlin AD, Heger K, Schubert AF, Reja R, Yan D et al. 2020. Integration of innate immune signalling by caspase-8 cleavage of N4BP1. Nature 587:27580
    [Google Scholar]
  62. 62.
    Annibaldi A, Walczak H. 2020. Death receptors and their ligands in inflammatory disease and cancer. Cold Spring Harb. Perspect. Biol. 12:a036384
    [Google Scholar]
  63. 63.
    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 174:147791.e19
    [Google Scholar]
  64. 64.
    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 362:106469
    [Google Scholar]
  65. 65.
    Sarhan J, Liu BC, Muendlein HI, Li P, Nilson R et al. 2018. Caspase-8 induces cleavage of gasdermin D to elicit pyroptosis during Yersinia infection. PNAS 115:E1088897
    [Google Scholar]
  66. 66.
    Wang Y, Gao W, Shi X, Ding J, Liu W et al. 2017. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature 547:99103
    [Google Scholar]
  67. 67.
    Dondelinger Y, Aguileta MA, Goossens V, Dubuisson C, Grootjans S et al. 2013. RIPK3 contributes to TNFR1-mediated RIPK1 kinase–dependent apoptosis in conditions of cIAP1/2 depletion or TAK1 kinase inhibition. Cell Death Differ 20:138192
    [Google Scholar]
  68. 68.
    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]
  69. 69.
    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]
  70. 70.
    Kist M, Komuves LG, Goncharov T, Dugger DL, Yu C et al. 2021. Impaired RIPK1 ubiquitination sensitizes mice to TNF toxicity and inflammatory cell death. Cell Death Differ 28:9851000
    [Google Scholar]
  71. 71.
    Huyghe J, Priem D, Van Hove L, Gilbert B, Fritsch J et al. 2022. ATG9A prevents TNF cytotoxicity by an unconventional lysosomal targeting pathway. Science 378:12017
    [Google Scholar]
  72. 72.
    Ang RL, Chan M, Legarda D, Sundberg JP, Sun SC et al. 2021. Immune dysregulation in SHARPIN-deficient mice is dependent on CYLD-mediated cell death. PNAS 118:e2001602118
    [Google Scholar]
  73. 73.
    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 44:55367
    [Google Scholar]
  74. 74.
    Schwarzer R, Jiao H, Wachsmuth L, Tresch A, Pasparakis M. 2020. FADD and caspase-8 regulate gut homeostasis and inflammation by controlling MLKL- and GSDMD-mediated death of intestinal epithelial cells. Immunity 52:97893.e6
    [Google Scholar]
  75. 75.
    Taraborrelli L, Peltzer N, Montinaro A, Kupka S, Rieser E et al. 2018. LUBAC prevents lethal dermatitis by inhibiting cell death induced by TNF, TRAIL and CD95L. Nat. Commun. 9:3910
    [Google Scholar]
  76. 76.
    Feoktistova M, Geserick P, Kellert B, Dimitrova DP, Langlais C et al. 2011. cIAPs block Ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms. Mol. Cell 43:44963
    [Google Scholar]
  77. 77.
    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]
  78. 78.
    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]
  79. 79.
    Cuchet-Lourenco 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 361:81013
    [Google Scholar]
  80. 80.
    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 116:97075
    [Google Scholar]
  81. 81.
    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 26:87789
    [Google Scholar]
  82. 82.
    Saleh D, Najjar M, Zelic M, Shah S, Nogusa S et al. 2017. Kinase activities of RIPK1 and RIPK3 can direct IFN-β synthesis induced by lipopolysaccharide. J. Immunol. 198:443547
    [Google Scholar]
  83. 83.
    Wang Y, Karki R, Mall R, Sharma BR, Kalathur RC et al. 2022. Molecular mechanism of RIPK1 and caspase-8 in homeostatic type I interferon production and regulation. Cell Rep 41:111434
    [Google Scholar]
  84. 84.
    Stark K, Goncharov T, Varfolomeev E, Xie L, Ngu H et al. 2021. Genetic inactivation of RIP1 kinase activity in rats protects against ischemic brain injury. Cell Death Dis 12:379
    [Google Scholar]
  85. 85.
    Van Eeckhoutte HP, Donovan C, Kim RY, Conlon TM, Ansari M et al. 2022. RIPK1 kinase-dependent inflammation and cell death contribute to the pathogenesis of COPD. Eur. Respir. J. 61:2201506
    [Google Scholar]
  86. 86.
    Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D et al. 2018. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ 25:486541
    [Google Scholar]
  87. 87.
    Liu X, Xia S, Zhang Z, Wu H, Lieberman J. 2021. Channelling inflammation: gasdermins in physiology and disease. Nat. Rev. Drug Discov. 20:384405
    [Google Scholar]
  88. 88.
    Kayagaki N, Dixit VM. 2019. Rescue from a fiery death: a therapeutic endeavor. Science 366:68889
    [Google Scholar]
  89. 89.
    Karki R, Lee E, Place D, Samir P, Mavuluri J et al. 2018. IRF8 regulates transcription of Naips for NLRC4 inflammasome activation. Cell 173:92033.e13
    [Google Scholar]
  90. 90.
    Wang J, Deobald K, Re F. 2019. Gasdermin D protects from melioidosis through pyroptosis and direct killing of bacteria. J. Immunol. 202:346873
    [Google Scholar]
  91. 91.
    Luchetti G, Roncaioli JL, Chavez RA, Schubert AF, Kofoed EM et al. 2021. Shigella ubiquitin ligase IpaH7.8 targets gasdermin D for degradation to prevent pyroptosis and enable infection. Cell Host Microbe 29:152130.e10
    [Google Scholar]
  92. 92.
    Hansen JM, de Jong MF, Wu Q, Zhang LS, Heisler DB et al. 2021. Pathogenic ubiquitination of GSDMB inhibits NK cell bactericidal functions. Cell 184:317891.e18
    [Google Scholar]
  93. 93.
    Xia S, Zhang Z, Magupalli VG, Pablo JL, Dong Y et al. 2021. Gasdermin D pore structure reveals preferential release of mature interleukin-1. Nature 593:60711
    [Google Scholar]
  94. 94.
    Afonina IS, Muller C, Martin SJ, Beyaert R. 2015. Proteolytic processing of interleukin-1 family cytokines: variations on a common theme. Immunity 42:9911004
    [Google Scholar]
  95. 95.
    Evavold CL, Ruan J, Tan Y, Xia S, Wu H, Kagan JC. 2018. The pore-forming protein gasdermin D regulates interleukin-1 secretion from living macrophages. Immunity 48:3544.e6
    [Google Scholar]
  96. 96.
    Ruhl S, Broz P. 2022. Regulation of lytic and non-lytic functions of gasdermin pores. J. Mol. Biol. 434:167246
    [Google Scholar]
  97. 97.
    Liu T, Yamaguchi Y, Shirasaki Y, Shikada K, Yamagishi M et al. 2014. Single-cell imaging of caspase-1 dynamics reveals an all-or-none inflammasome signaling response. Cell Rep 8:97482
    [Google Scholar]
  98. 98.
    Polykratis A, Martens A, Eren RO, Shirasaki Y, Yamagishi M et al. 2019. A20 prevents inflammasome-dependent arthritis by inhibiting macrophage necroptosis through its ZnF7 ubiquitin-binding domain. Nat. Cell Biol. 21:73142
    [Google Scholar]
  99. 99.
    Kayagaki N, Kornfeld OS, Lee BL, Stowe IB, O'Rourke K et al. 2021. NINJ1 mediates plasma membrane rupture during lytic cell death. Nature 591:13136
    [Google Scholar]
  100. 100.
    Bjanes E, Sillas RG, Matsuda R, Demarco B, Fettrelet T et al. 2021. Genetic targeting of Card19 is linked to disrupted NINJ1 expression, impaired cell lysis, and increased susceptibility to Yersinia infection. PLOS Pathog. 17:e1009967
    [Google Scholar]
  101. 101.
    Degen M, Santo JC, Pluhackova K, Cebrero G, Ramos S et al. 2023. Structural basis of NINJ1-mediated plasma membrane rupture in cell death. Nature 618:106571
    [Google Scholar]
  102. 102.
    Araki T, Milbrandt J. 1996. Ninjurin, a novel adhesion molecule, is induced by nerve injury and promotes axonal growth. Neuron 17:35361
    [Google Scholar]
  103. 103.
    Chao KL, Kulakova L, Herzberg O. 2017. Gene polymorphism linked to increased asthma and IBD risk alters gasdermin-B structure, a sulfatide and phosphoinositide binding protein. PNAS 114:E112837
    [Google Scholar]
  104. 104.
    De Schutter E, Ramon J, Pfeuty B, De Tender C, Stremersch S et al. 2021. Plasma membrane perforation by GSDME during apoptosis-driven secondary necrosis. Cell. Mol. Life Sci. 79:19
    [Google Scholar]
  105. 105.
    Chen KW, Demarco B, Ramos S, Heilig R, Goris M et al. 2021. RIPK1 activates distinct gasdermins in macrophages and neutrophils upon pathogen blockade of innate immune signaling. PNAS 118:e2101189118
    [Google Scholar]
  106. 106.
    Zhang Z, Zhang Y, Xia S, Kong Q, Li S et al. 2020. Gasdermin E suppresses tumour growth by activating anti-tumour immunity. Nature 579:41520
    [Google Scholar]
  107. 107.
    Chekeni FB, Elliott MR, Sandilos JK, Walk SF, Kinchen JM et al. 2010. Pannexin 1 channels mediate ‘find-me’ signal release and membrane permeability during apoptosis. Nature 467:86367
    [Google Scholar]
  108. 108.
    Green DR, Ferguson T, Zitvogel L, Kroemer G. 2009. Immunogenic and tolerogenic cell death. Nat. Rev. Immunol. 9:35363
    [Google Scholar]
  109. 109.
    Zhou Z, He H, Wang K, Shi X, Wang Y et al. 2020. Granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells. Science 368:eaaz7548
    [Google Scholar]
  110. 110.
    Rana N, Privitera G, Kondolf HC, Bulek K, Lechuga S et al. 2022. GSDMB is increased in IBD and regulates epithelial restitution/repair independent of pyroptosis. Cell 185:28398.e17
    [Google Scholar]
  111. 111.
    Ivanov AI, Rana N, Privitera G, Pizarro TT. 2023. The enigmatic roles of epithelial gasdermin B: recent discoveries and controversies. Trends Cell Biol 33:4859
    [Google Scholar]
  112. 112.
    Deng W, Bai Y, Deng F, Pan Y, Mei S et al. 2022. Streptococcal pyrogenic exotoxin B cleaves GSDMA and triggers pyroptosis. Nature 602:496502
    [Google Scholar]
  113. 113.
    LaRock DL, Johnson AF, Wilde S, Sands JS, Monteiro MP, LaRock CN. 2022. Group A Streptococcus induces GSDMA-dependent pyroptosis in keratinocytes. Nature 605:52731
    [Google Scholar]
  114. 114.
    Ding J, Wang K, Liu W, She Y, Sun Q et al. 2016. Pore-forming activity and structural autoinhibition of the gasdermin family. Nature 535:11116
    [Google Scholar]
  115. 115.
    Hou J, Zhao R, Xia W, Chang CW, You Y et al. 2020. PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumour necrosis. Nat. Cell Biol. 22:126475
    [Google Scholar]
  116. 116.
    Zhao M, Ren K, Xiong X, Xin Y, Zou Y et al. 2022. Epithelial STAT6 O-GlcNAcylation drives a concerted anti-helminth alarmin response dependent on tuft cell hyperplasia and Gasdermin C. Immunity 55:62338.e5
    [Google Scholar]
  117. 117.
    Johnson AG, Wein T, Mayer ML, Duncan-Lowey B, Yirmiya E et al. 2022. Bacterial gasdermins reveal an ancient mechanism of cell death. Science 375:22125
    [Google Scholar]
  118. 118.
    Kayagaki N, Stowe IB, Lee BL, O'Rourke K, Anderson K et al. 2015. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526:66671
    [Google Scholar]
  119. 119.
    Zhang H, Zeng L, Xie M, Liu J, Zhou B et al. 2020. TMEM173 drives lethal coagulation in sepsis. Cell Host Microbe 27:55670.e6
    [Google Scholar]
  120. 120.
    Cheng KT, Xiong S, Ye Z, Hong Z, Di A et al. 2017. Caspase-11-mediated endothelial pyroptosis underlies endotoxemia-induced lung injury. J. Clin. Investig. 127:412435
    [Google Scholar]
  121. 121.
    Yang X, Cheng X, Tang Y, Qiu X, Wang Y et al. 2019. Bacterial endotoxin activates the coagulation cascade through gasdermin D–dependent phosphatidylserine exposure. Immunity 51:98396.e6
    [Google Scholar]
  122. 122.
    Sollberger G, Choidas A, Burn GL, Habenberger P, Di Lucrezia R et al. 2018. Gasdermin D plays a vital role in the generation of neutrophil extracellular traps. Sci. Immunol. 3:eaar6689
    [Google Scholar]
  123. 123.
    Chen KW, Monteleone M, Boucher D, Sollberger G, Ramnath D et al. 2018. Noncanonical inflammasome signaling elicits gasdermin D–dependent neutrophil extracellular traps. Sci. Immunol. 3:eaar6676
    [Google Scholar]
  124. 124.
    Chauhan D, Demon D, Vande Walle L, Paerewijck O, Zecchin A et al. 2022. GSDMD drives canonical inflammasome-induced neutrophil pyroptosis and is dispensable for NETosis. EMBO Rep 23:e54277
    [Google Scholar]
  125. 125.
    Chen W, Chen S, Yan C, Zhang Y, Zhang R et al. 2022. Allergen protease-activated stress granule assembly and gasdermin D fragmentation control interleukin-33 secretion. Nat. Immunol. 23:102130
    [Google Scholar]
  126. 126.
    Xiao J, Wang C, Yao JC, Alippe Y, Xu C et al. 2018. Gasdermin D mediates the pathogenesis of neonatal-onset multisystem inflammatory disease in mice. PLOS Biol 16:e3000047
    [Google Scholar]
  127. 127.
    Kanneganti A, Malireddi RKS, Saavedra PHV, Vande Walle L, Van Gorp H et al. 2018. GSDMD is critical for autoinflammatory pathology in a mouse model of familial Mediterranean fever. J. Exp. Med. 215:151929
    [Google Scholar]
  128. 128.
    Kyriazopoulou E, Huet T, Cavalli G, Gori A, Kyprianou M et al. 2021. Effect of anakinra on mortality in patients with COVID-19: a systematic review and patient-level meta-analysis. Lancet Rheumatol 3:e69097
    [Google Scholar]
  129. 129.
    Sefik E, Qu R, Junqueira C, Kaffe E, Mirza H et al. 2022. Inflammasome activation in infected macrophages drives COVID-19 pathology. Nature 606:58593
    [Google Scholar]
  130. 130.
    Rathkey JK, Xiao TS, Abbott DW. 2020. Human polymorphisms in GSDMD alter the inflammatory response. J. Biol. Chem. 295:322838
    [Google Scholar]
  131. 131.
    Dong S, Shi Y, Dong X, Xiao X, Qi J et al. 2022. Gasdermin E is required for induction of pyroptosis and severe disease during enterovirus 71 infection. J. Biol. Chem. 298:101850
    [Google Scholar]
  132. 132.
    Liu Y, Fang Y, Chen X, Wang Z, Liang X et al. 2020. Gasdermin E–mediated target cell pyroptosis by CAR T cells triggers cytokine release syndrome. Sci. Immunol. 5:eaax7969
    [Google Scholar]
  133. 133.
    Mangan MSJ, Olhava EJ, Roush WR, Seidel HM, Glick GD, Latz E. 2018. Targeting the NLRP3 inflammasome in inflammatory diseases. Nat. Rev. Drug Discov. 17:588606
    [Google Scholar]
  134. 134.
    Xiao L, Magupalli VG, Wu H. 2023. Cryo-EM structures of the active NLRP3 inflammasome disc. Nature 613:595600
    [Google Scholar]
  135. 135.
    Svensson EC, Madar A, Campbell CD, He Y, Sultan M et al. 2022. TET2-driven clonal hematopoiesis and response to canakinumab: an exploratory analysis of the CANTOS randomized clinical trial. JAMA Cardiol 7:52128
    [Google Scholar]
  136. 136.
    Fuster JJ, MacLauchlan S, Zuriaga MA, Polackal MN, Ostriker AC et al. 2017. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 355:84247
    [Google Scholar]
  137. 137.
    Fidler TP, Xue C, Yalcinkaya M, Hardaway B, Abramowicz S et al. 2021. The AIM2 inflammasome exacerbates atherosclerosis in clonal haematopoiesis. Nature 592:296301
    [Google Scholar]
  138. 138.
    Shi H, Wang Y, Li X, Zhan X, Tang M et al. 2016. NLRP3 activation and mitosis are mutually exclusive events coordinated by NEK7, a new inflammasome component. Nat. Immunol. 17:25058
    [Google Scholar]
  139. 139.
    Schmacke NA, O'Duill F, Gaidt MM, Szymanska I, Kamper JM et al. 2022. IKKβ primes inflammasome formation by recruiting NLRP3 to the trans-Golgi network. Immunity 55:227184.e7
    [Google Scholar]
  140. 140.
    Shakoory B, Carcillo JA, Chatham WW, Amdur RL, Zhao H et al. 2016. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior phase III trial. Crit. Care Med. 44:27581
    [Google Scholar]
  141. 141.
    Hu JJ, Liu X, Xia S, Zhang Z, Zhang Y et al. 2020. FDA-approved disulfiram inhibits pyroptosis by blocking gasdermin D pore formation. Nat. Immunol. 21:73645
    [Google Scholar]
  142. 142.
    Bertheloot D, Wanderley CW, Schneider AH, Schiffelers LD, Wuerth JD et al. 2022. Nanobodies dismantle post-pyroptotic ASC specks and counteract inflammation in vivo. EMBO Mol. Med. 14:e15415
    [Google Scholar]
  143. 143.
    Choi S, Woo JK, Jang YS, Kang JH, Hwang JI et al. 2018. Ninjurin1 plays a crucial role in pulmonary fibrosis by promoting interaction between macrophages and alveolar epithelial cells. Sci. Rep. 8:17542
    [Google Scholar]
  144. 144.
    Ahn BJ, Lee HJ, Shin MW, Choi JH, Jeong JW, Kim KW. 2009. Ninjurin1 is expressed in myeloid cells and mediates endothelium adhesion in the brains of EAE rats. Biochem. Biophys. Res. Commun. 387:32125
    [Google Scholar]
  145. 145.
    Kristjansson RP, Oddsson A, Helgason H, Sveinbjornsson G, Arnadottir GA et al. 2016. Common and rare variants associating with serum levels of creatine kinase and lactate dehydrogenase. Nat. Commun. 7:10572
    [Google Scholar]
  146. 146.
    Borges JP, Saetra RSR, Volchuk A, Bugge M, Devant P et al. 2022. Glycine inhibits NINJ1 membrane clustering to suppress plasma membrane rupture in cell death. eLife 11:e78609
    [Google Scholar]
  147. 147.
    Loomis WP, den Hartigh AB, Cookson BT, Fink SL. 2019. Diverse small molecules prevent macrophage lysis during pyroptosis. Cell Death Dis. 10:326
    [Google Scholar]
  148. 148.
    Doerflinger M, Deng Y, Whitney P, Salvamoser R, Engel S et al. 2020. Flexible usage and interconnectivity of diverse cell death pathways protect against intracellular infection. Immunity 53:53347.e7
    [Google Scholar]
  149. 149.
    Nogusa S, Thapa RJ, Dillon CP, Liedmann S, Oguin TH 3rd et al. 2016. RIPK3 activates parallel pathways of MLKL-driven necroptosis and FADD-mediated apoptosis to protect against influenza A virus. Cell Host Microbe 20:1324
    [Google Scholar]
  150. 150.
    Kuriakose T, Man SM, Malireddi RK, 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]
  151. 151.
    Lee S, Karki R, Wang Y, Nguyen LN, Kalathur RC, Kanneganti TD. 2021. AIM2 forms a complex with pyrin and ZBP1 to drive PANoptosis and host defence. Nature 597:41519
    [Google Scholar]
  152. 152.
    Newton K, Wickliffe KE, Maltzman A, Dugger DL, Reja R et al. 2019. Activity of caspase-8 determines plasticity between cell death pathways. Nature 575:67982
    [Google Scholar]
  153. 153.
    Fritsch M, Gunther SD, Schwarzer R, Albert MC, Schorn F et al. 2019. Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis. Nature 575:68387
    [Google Scholar]
  154. 154.
    Zhang T, Yin C, Fedorov A, Qiao L, Bao H et al. 2022. ADAR1 masks the cancer immunotherapeutic promise of ZBP1-driven necroptosis. Nature 606:594602
    [Google Scholar]
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