Knocking ’em Dead: Pore-Forming Proteins in Immune Defense

Literature Cited

1. 1. 

   Rosado CJ, Kondos S, Bull TE, Kuiper MJ, Law RH et al. 2008. The MACPF/CDC family of pore-forming toxins. Cell Microbiol 10:1765–74
   [Google Scholar]
2. 2. 

   Dotiwala F, Lieberman J. 2019. Granulysin: killer lymphocyte safeguard against microbes. Curr. Opin. Immunol. 60:19–29
   [Google Scholar]
3. 3. 

   Liu X, Lieberman J. 2017. A mechanistic understanding of pyroptosis: the fiery death triggered by invasive infection. Adv. Immunol. 135:81–117
   [Google Scholar]
4. 4. 

   Shan B, Pan H, Najafov A, Yuan J 2018. Necroptosis in development and diseases. Genes Dev 32:327–40
   [Google Scholar]
5. 5. 

   Thiery J, Lieberman J. 2014. Perforin: a key pore-forming protein for immune control of viruses and cancer. Subcell. Biochem. 80:197–220
   [Google Scholar]
6. 6. 

   Weinlich R, Oberst A, Beere HM, Green DR 2017. Necroptosis in development, inflammation and disease. Nat. Rev. Mol. Cell Biol. 18:127–36
   [Google Scholar]
7. 7. 

   Anderson DH, Sawaya MR, Cascio D, Ernst W, Modlin R et al. 2003. Granulysin crystal structure and a structure-derived lytic mechanism. J. Mol. Biol. 325:355–65
   [Google Scholar]
8. 8. 

   Dudkina NV, Spicer BA, Reboul CF, Conroy PJ, Lukoyanova N et al. 2016. Structure of the poly-C9 component of the complement membrane attack complex. Nat. Commun. 7:10588
   [Google Scholar]
9. 9. 

   Law RH, Lukoyanova N, Voskoboinik I, Caradoc-Davies TT, Baran K et al. 2010. The structural basis for membrane binding and pore formation by lymphocyte perforin. Nature 468:447–51
   [Google Scholar]
10. 10. 

    Ruan J, Xia S, Liu X, Lieberman J, Wu H 2018. Cryo-EM structure of the gasdermin A3 membrane pore. Nature 557:62–67
    [Google Scholar]
11. 11. 

    Serna M, Giles JL, Morgan BP, Bubeck D 2016. Structural basis of complement membrane attack complex formation. Nat. Commun. 7:10587
    [Google Scholar]
12. 12. 

    Su L, Quade B, Wang H, Sun L, Wang X, Rizo J 2014. A plug release mechanism for membrane permeation by MLKL. Structure 22:1489–500
    [Google Scholar]
13. 13. 

    Menny A, Serna M, Boyd CM, Gardner S, Joseph AP et al. 2018. CryoEM reveals how the complement membrane attack complex ruptures lipid bilayers. Nat. Commun. 9:5316
    [Google Scholar]
14. 14. 

    Pang SS, Bayly-Jones C, Radjainia M, Spicer BA, Law RHP et al. 2019. The cryo-EM structure of the acid activatable pore-forming immune effector Macrophage-expressed gene 1. Nat. Commun. 10:4288
    [Google Scholar]
15. 15. 

    Ding J, Wang K, Liu W, She Y, Sun Q et al. 2016. Pore-forming activity and structural autoinhibition of the gasdermin family. Nature 535:111–16
    [Google Scholar]
16. 16. 

    Liu X, Zhang Z, Ruan J, Pan Y, Magupalli VG et al. 2016. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 535:153–58
    [Google Scholar]
17. 17. 

    Pipkin ME, Lieberman J. 2007. Delivering the kiss of death: progress on understanding how perforin works. Curr. Opin. Immunol. 19:301–8
    [Google Scholar]
18. 18. 

    Wang J, Deobald K, Re F 2019. Gasdermin D protects from melioidosis through pyroptosis and direct killing of bacteria. J. Immunol. 202:3468–73
    [Google Scholar]
19. 19. 

    Chowdhury D, Lieberman J. 2008. Death by a thousand cuts: granzyme pathways of programmed cell death. Annu. Rev. Immunol. 26:389–420
    [Google Scholar]
20. 20. 

    Rogers C, Fernandes-Alnemri T, Mayes L, Alnemri D, Cingolani G, Alnemri ES 2017. Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death. Nat. Commun. 8:14128
    [Google Scholar]
21. 21. 

    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 547:99–103
    [Google Scholar]
22. 22. 

    Antonopoulos C, Russo HM, El Sanadi C, Martin BN, Li X et al. 2015. Caspase-8 as an effector and regulator of NLRP3 inflammasome signaling. J. Biol. Chem. 290:20167–84
    [Google Scholar]
23. 23. 

    Mascarenhas DPA, Cerqueira DM, Pereira MSF, Castanheira FVS, Fernandes TD et al. 2017. Inhibition of caspase-1 or gasdermin-D enable caspase-8 activation in the Naip5/NLRC4/ASC inflammasome. PLOS Pathog 13:e1006502
    [Google Scholar]
24. 24. 

    Laudisi F, Spreafico R, Evrard M, Hughes TR, Mandriani B et al. 2013. Cutting edge: the NLRP3 inflammasome links complement-mediated inflammation and IL-1β release. J. Immunol. 191:1006–10
    [Google Scholar]
25. 25. 

    Yao Y, Chen S, Cao M, Fan X, Yang T et al. 2017. Antigen-specific CD8⁺ T cell feedback activates NLRP3 inflammasome in antigen-presenting cells through perforin. Nat. Commun. 8:15402
    [Google Scholar]
26. 26. 

    Conos SA, Chen KW, De Nardo D, Hara H, Whitehead L et al. 2017. Active MLKL triggers the NLRP3 inflammasome in a cell-intrinsic manner. PNAS 114:E961–69
    [Google Scholar]
27. 27. 

    McCormack R, Bahnan W, Shrestha N, Boucher J, Barreto M et al. 2016. Perforin-2 protects host cells and mice by restricting the vacuole to cytosol transitioning of a bacterial pathogen. Infect. Immun. 84:1083–91
    [Google Scholar]
28. 28. 

    Podack ER, Munson GP. 2016. Killing of microbes and cancer by the immune system with three mammalian pore-forming killer proteins. Front. Immunol. 7:464
    [Google Scholar]
29. 29. 

    Zipfel PF, Skerka C. 2009. Complement regulators and inhibitory proteins. Nat. Rev. Immunol. 9:729–40
    [Google Scholar]
30. 30. 

    Guo RF, Ward PA. 2005. Role of C5a in inflammatory responses. Annu. Rev. Immunol. 23:821–52
    [Google Scholar]
31. 31. 

    Ricklin D, Hajishengallis G, Yang K, Lambris JD 2010. Complement: a key system for immune surveillance and homeostasis. Nat. Immunol. 11:785–97
    [Google Scholar]
32. 32. 

    Reboul CF, Whisstock JC, Dunstone MA 2016. Giant MACPF/CDC pore forming toxins: a class of their own. Biochim. Biophys. Acta Biomembr. 1858:475–86
    [Google Scholar]
33. 33. 

    Tschopp J, Muller-Eberhard HJ, Podack ER 1982. Formation of transmembrane tubules by spontaneous polymerization of the hydrophilic complement protein C9. Nature 298:534–38
    [Google Scholar]
34. 34. 

    Anderluh G, Kisovec M, Krasevec N, Gilbert RJ 2014. Distribution of MACPF/CDC proteins. Subcell. Biochem. 80:7–30
    [Google Scholar]
35. 35. 

    Botto M, Kirschfink M, Macor P, Pickering MC, Wurzner R, Tedesco F 2009. Complement in human diseases: lessons from complement deficiencies. Mol. Immunol. 46:2774–83
    [Google Scholar]
36. 36. 

    Walport MJ. 2001. Complement: first of two parts. N. Engl. J. Med. 344:1058–66
    [Google Scholar]
37. 37. 

    Lindahl G, Sjobring U, Johnsson E 2000. Human complement regulators: a major target for pathogenic microorganisms. Curr. Opin. Immunol. 12:44–51
    [Google Scholar]
38. 38. 

    Pipkin ME, Ljutic B, Cruz-Guilloty F, Nouzova M, Rao A et al. 2007. Chromosome transfer activates and delineates a locus control region for perforin. Immunity 26:29–41
    [Google Scholar]
39. 39. 

    Voskoboinik I, Whisstock JC, Trapani JA 2015. Perforin and granzymes: function, dysfunction and human pathology. Nat. Rev. Immunol. 15:388–400
    [Google Scholar]
40. 40. 

    Shepard LA, Heuck AP, Hamman BD, Rossjohn J, Parker MW et al. 1998. Identification of a membrane-spanning domain of the thiol-activated pore-forming toxin Clostridium perfringens perfringolysin O: an α-helical to β-sheet transition identified by fluorescence spectroscopy. Biochemistry 37:14563–74
    [Google Scholar]
41. 41. 

    Peters PJ, Borst J, Oorschot V, Fukuda M, Krahenbuhl O et al. 1991. Cytotoxic T lymphocyte granules are secretory lysosomes, containing both perforin and granzymes. J. Exp. Med. 173:1099–109
    [Google Scholar]
42. 42. 

    Stinchcombe JC, Bossi G, Booth S, Griffiths GM 2001. The immunological synapse of CTL contains a secretory domain and membrane bridges. Immunity 15:751–61
    [Google Scholar]
43. 43. 

    Keefe D, Shi L, Feske S, Massol R, Navarro F et al. 2005. Perforin triggers a plasma membrane-repair response that facilitates CTL induction of apoptosis. Immunity 23:249–62
    [Google Scholar]
44. 44. 

    Thiery J, Keefe D, Boulant S, Boucrot E, Walch M et al. 2011. Perforin pores in the endosomal membrane trigger the release of endocytosed granzyme B into the cytosol of target cells. Nat. Immunol. 12:770–77
    [Google Scholar]
45. 45. 

    Thiery J, Keefe D, Saffarian S, Martinvalet D, Walch M et al. 2010. Perforin activates clathrin- and dynamin-dependent endocytosis, which is required for plasma membrane repair and delivery of granzyme B for granzyme-mediated apoptosis. Blood 115:1582–93
    [Google Scholar]
46. 46. 

    Bird CH, Sun J, Ung K, Karambalis D, Whisstock JC et al. 2005. Cationic sites on granzyme B contribute to cytotoxicity by promoting its uptake into target cells. Mol. Cell. Biol. 25:7854–67
    [Google Scholar]
47. 47. 

    Shi L, Keefe D, Durand E, Feng H, Zhang D, Lieberman J 2005. Granzyme B binds to target cells mostly by charge and must be added at the same time as perforin to trigger apoptosis. J. Immunol. 174:5456–61
    [Google Scholar]
48. 48. 

    Darmon AJ, Nicholson DW, Bleackley RC 1995. Activation of the apoptotic protease CPP32 by cytotoxic T-cell-derived granzyme B. Nature 377:446–48
    [Google Scholar]
49. 49. 

    Yagi H, Conroy PJ, Leung EW, Law RH, Trapani JA et al. 2015. Structural basis for Ca²⁺-mediated interaction of the perforin C2 domain with lipid membranes. J. Biol. Chem. 290:25213–26
    [Google Scholar]
50. 50. 

    Gilbert RJ. 2010. Cholesterol-Dependent Cytolysins New York: Springer
51. 51. 

    Balaji KN, Schaschke N, Machleidt W, Catalfamo M, Henkart PA 2002. Surface cathepsin B protects cytotoxic lymphocytes from self-destruction after degranulation. J. Exp. Med. 196:493–503
    [Google Scholar]
52. 52. 

    Baran K, Ciccone A, Peters C, Yagita H, Bird PI et al. 2006. Cytotoxic T lymphocytes from cathepsin B-deficient mice survive normally in vitro and in vivo after encountering and killing target cells. J. Biol. Chem. 281:30485–91
    [Google Scholar]
53. 53. 

    Kagi D, Ledermann B, Burki K, Seiler P, Odermatt B et al. 1994. Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Nature 369:31–37
    [Google Scholar]
54. 54. 

    van den Broek ME, Kagi D, Ossendorp F, Toes R, Vamvakas S et al. 1996. Decreased tumor surveillance in perforin-deficient mice. J. Exp. Med. 184:1781–90
    [Google Scholar]
55. 55. 

    Zhang K, Jordan MB, Marsh RA, Johnson JA, Kissell D et al. 2011. Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. Blood 118:5794–98
    [Google Scholar]
56. 56. 

    Jenkins MR, Rudd-Schmidt JA, Lopez JA, Ramsbottom KM, Mannering SI et al. 2015. Failed CTL/NK cell killing and cytokine hypersecretion are directly linked through prolonged synapse time. J. Exp. Med. 212:307–17
    [Google Scholar]
57. 57. 

    Xiong P, Shiratsuchi M, Matsushima T, Liao J, Tanaka E et al. 2017. Regulation of expression and trafficking of perforin-2 by LPS and TNF-α. Cell Immunol 320:1–10
    [Google Scholar]
58. 58. 

    McCormack R, de Armas LR, Shiratsuchi M, Ramos JE, Podack ER 2013. Inhibition of intracellular bacterial replication in fibroblasts is dependent on the perforin-like protein (perforin-2) encoded by macrophage-expressed gene 1. J. Innate Immun. 5:185–94
    [Google Scholar]
59. 59. 

    McCormack R, Podack ER. 2015. Perforin-2/Mpeg1 and other pore-forming proteins throughout evolution. J. Leukoc. Biol. 98:761–68
    [Google Scholar]
60. 60. 

    Bai F, McCormack RM, Hower S, Plano GV, Lichtenheld MG, Munson GP 2018. Perforin-2 breaches the envelope of phagocytosed bacteria allowing antimicrobial effectors access to intracellular targets. J. Immunol. 201:2710–20
    [Google Scholar]
61. 61. 

    Fields KA, McCormack R, de Armas LR, Podack ER 2013. Perforin-2 restricts growth of Chlamydia trachomatis in macrophages. Infect. Immun. 81:3045–54
    [Google Scholar]
62. 62. 

    McCormack RM, Szymanski EP, Hsu AP, Perez E, Olivier KN et al. 2017. MPEG1/perforin-2 mutations in human pulmonary nontuberculous mycobacterial infections. JCI Insight 2:89635
    [Google Scholar]
63. 63. 

    McCormack RM, de Armas LR, Shiratsuchi M, Fiorentino DG, Olsson ML et al. 2015. Perforin-2 is essential for intracellular defense of parenchymal cells and phagocytes against pathogenic bacteria. eLife 4:e06508
    [Google Scholar]
64. 64. 

    Tamura M, Tanaka S, Fujii T, Aoki A, Komiyama H et al. 2007. Members of a novel gene family, Gsdm, are expressed exclusively in the epithelium of the skin and gastrointestinal tract in a highly tissue-specific manner. Genomics 89:618–29
    [Google Scholar]
65. 65. 

    Burgener SS, Leborgne NGF, Snipas SJ, Salvesen GS, Bird PI, Benarafa C 2019. Cathepsin G inhibition by Serpinb1 and Serpinb6 prevents programmed necrosis in neutrophils and monocytes and reduces GSDMD-driven inflammation. Cell Rep 27:3646–56.e5
    [Google Scholar]
66. 66. 

    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]
67. 67. 

    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:E10888–97
    [Google Scholar]
68. 68. 

    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]
69. 69. 

    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:E1128–37
    [Google Scholar]
70. 70. 

    Collin RW, Kalay E, Oostrik J, Caylan R, Wollnik B et al. 2007. Involvement of DFNB59 mutations in autosomal recessive nonsyndromic hearing impairment. Hum. Mutat. 28:718–23
    [Google Scholar]
71. 71. 

    Runkel F, Marquardt A, Stoeger C, Kochmann E, Simon D et al. 2004. The dominant alopecia phenotypes Bareskin, Rex-denuded, and Reduced Coat 2 are caused by mutations in gasdermin 3. . Genomics 84:824–35
    [Google Scholar]
72. 72. 

    Van Laer L, Huizing EH, Verstreken M, van Zuijlen D, Wauters JG et al. 1998. Nonsyndromic hearing impairment is associated with a mutation in DFNA5. Nat. Genet 20:194–97
    [Google Scholar]
73. 73. 

    Wu H, Romieu I, Sienra-Monge JJ, Li H, del Rio-Navarro BE, London SJ 2009. Genetic variation in ORM1-like 3 (ORMDL3) and gasdermin-like (GSDML) and childhood asthma. Allergy 64:629–35
    [Google Scholar]
74. 74. 

    Li J, Zhou Y, Yang T, Wang N, Lian X, Yang L 2010. Gsdma3 is required for hair follicle differentiation in mice. Biochem. Biophys. Res. Commun. 403:18–23
    [Google Scholar]
75. 75. 

    Tanaka S, Tamura M, Aoki A, Fujii T, Komiyama H et al. 2007. A new Gsdma3 mutation affecting anagen phase of first hair cycle. Biochem. Biophys. Res. Commun. 359:902–7
    [Google Scholar]
76. 76. 

    Kumar S, Rathkolb B, Budde BS, Nurnberg P, de Angelis MH et al. 2012. Gsdma3^I359N is a novel ENU-induced mutant mouse line for studying the function of Gasdermin A3 in the hair follicle and epidermis. J. Dermatol. Sci. 67:190–92
    [Google Scholar]
77. 77. 

    Lunny DP, Weed E, Nolan PM, Marquardt A, Augustin M, Porter RM 2005. Mutations in gasdermin 3 cause aberrant differentiation of the hair follicle and sebaceous gland. J. Investig. Dermatol. 124:615–21
    [Google Scholar]
78. 78. 

    Porter RM, Jahoda CA, Lunny DP, Henderson G, Ross J et al. 2002. Defolliculated (Dfl): a dominant mouse mutation leading to poor sebaceous gland differentiation and total elimination of pelage follicles. J. Investig. Dermatol. 119:32–37
    [Google Scholar]
79. 79. 

    Shi P, Tang A, Xian L, Hou S, Zou D et al. 2015. Loss of conserved Gsdma3 self-regulation causes autophagy and cell death. Biochem. J. 468:325–36
    [Google Scholar]
80. 80. 

    Kang MJ, Yu HS, Seo JH, Kim HY, Jung YH et al. 2012. GSDMB/ORMDL3 variants contribute to asthma susceptibility and eosinophil-mediated bronchial hyperresponsiveness. Hum. Immunol. 73:954–59
    [Google Scholar]
81. 81. 

    Das S, Miller M, Beppu AK, Mueller J, McGeough MD et al. 2016. GSDMB induces an asthma phenotype characterized by increased airway responsiveness and remodeling without lung inflammation. PNAS 113:13132–37
    [Google Scholar]
82. 82. 

    Delmaghani S, del Castillo FJ, Michel V, Leibovici M, Aghaie A et al. 2006. Mutations in the gene encoding pejvakin, a newly identified protein of the afferent auditory pathway, cause DFNB59 auditory neuropathy. Nat. Genet. 38:770–78
    [Google Scholar]
83. 83. 

    Delmaghani S, Defourny J, Aghaie A, Beurg M, Dulon D et al. 2015. Hypervulnerability to sound exposure through impaired adaptive proliferation of peroxisomes. Cell 163:894–906
    [Google Scholar]
84. 84. 

    Christofferson DE, Yuan J. 2010. Necroptosis as an alternative form of programmed cell death. Curr. Opin. Cell Biol. 22:263–68
    [Google Scholar]
85. 85. 

    Murphy JM, Czabotar PE, Hildebrand JM, Lucet IS, Zhang JG et al. 2013. The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism. Immunity 39:443–53
    [Google Scholar]
86. 86. 

    Cai Z, Jitkaew S, Zhao J, Chiang HC, Choksi S et al. 2014. Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis. Nat. Cell Biol. 16:55–65
    [Google Scholar]
87. 87. 

    Chen X, Li W, Ren J, Huang D, He WT et al. 2014. Translocation of mixed lineage kinase domain-like protein to plasma membrane leads to necrotic cell death. Cell Res 24:105–21
    [Google Scholar]
88. 88. 

    Dondelinger Y, Declercq W, Montessuit S, Roelandt R, Goncalves A et al. 2014. MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates. Cell Rep 7:971–81
    [Google Scholar]
89. 89. 

    Hildebrand JM, Tanzer MC, Lucet IS, Young SN, Spall SK et al. 2014. Activation of the pseudokinase MLKL unleashes the four-helix bundle domain to induce membrane localization and necroptotic cell death. PNAS 111:15072–77
    [Google Scholar]
90. 90. 

    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]
91. 91. 

    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]
92. 92. 

    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]
93. 93. 

    Wu J, Huang Z, Ren J, Zhang Z, He P et al. 2013. Mlkl knockout mice demonstrate the indispensable role of Mlkl in necroptosis. Cell Res 23:994–1006
    [Google Scholar]
94. 94. 

    Chan FK. 2012. Fueling the flames: Mammalian programmed necrosis in inflammatory diseases. Cold Spring Harb. Perspect. Biol. 4:a008805
    [Google Scholar]
95. 95. 

    Linkermann A, Hackl MJ, Kunzendorf U, Walczak H, Krautwald S, Jevnikar AM 2013. Necroptosis in immunity and ischemia-reperfusion injury. Am. J. Transplant. 13:2797–804
    [Google Scholar]
96. 96. 

    Sun L, Wang X. 2014. A new kind of cell suicide: mechanisms and functions of programmed necrosis. Trends Biochem. Sci. 39:587–93
    [Google Scholar]
97. 97. 

    Pasparakis M, Vandenabeele P. 2015. Necroptosis and its role in inflammation. Nature 517:311–20
    [Google Scholar]
98. 98. 

    Mocarski ES, Guo H, Kaiser WJ 2015. Necroptosis: The Trojan horse in cell autonomous antiviral host defense. Virology 479–480:160–66
    [Google Scholar]
99. 99. 

    Chen X, Zhuang C, Ren Y, Zhang H, Qin X et al. 2019. Identification of the Raf kinase inhibitor TAK-632 and its analogues as potent inhibitors of necroptosis by targeting RIPK1 and RIPK3. Br. J. Pharmacol. 176:2095–108
    [Google Scholar]
100. 100. 

     Hou J, Ju J, Zhang Z, Zhao C, Li Z et al. 2019. Discovery of potent necroptosis inhibitors targeting RIPK1 kinase activity for the treatment of inflammatory disorder and cancer metastasis. Cell Death Dis 10:493
     [Google Scholar]
101. 101. 

     Vandenabeele P, Grootjans S, Callewaert N, Takahashi N 2013. Necrostatin-1 blocks both RIPK1 and IDO: consequences for the study of cell death in experimental disease models. Cell Death Differ 20:185–87
     [Google Scholar]
102. 102. 

     Bertrand MJ, 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]
103. 103. 

     Kang TB, Yang SH, Toth B, Kovalenko A, Wallach D 2013. Caspase-8 blocks kinase RIPK3-mediated activation of the NLRP3 inflammasome. Immunity 38:27–40
     [Google Scholar]
104. 104. 

     Lawlor KE, Khan N, Mildenhall A, Gerlic M, Croker BA et al. 2015. RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL. Nat. Commun. 6:6282
     [Google Scholar]
105. 105. 

     Moriwaki K, Chan FK. 2014. Necrosis-dependent and independent signaling of the RIP kinases in inflammation. Cytokine Growth Factor Rev 25:167–74
     [Google Scholar]
106. 106. 

     Varfolomeev E, Blankenship JW, Wayson SM, Fedorova AV, Kayagaki N et al. 2007. IAP antagonists induce autoubiquitination of c-IAPs, NF-κB activation, and TNFα-dependent apoptosis. Cell 131:669–81
     [Google Scholar]
107. 107. 

     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]
108. 108. 

     Mocarski ES, Kaiser WJ, Livingston-Rosanoff D, Upton JW, Daley-Bauer LP 2014. True grit: programmed necrosis in antiviral host defense, inflammation, and immunogenicity. J. Immunol. 192:2019–26
     [Google Scholar]
109. 109. 

     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 20:13–24
     [Google Scholar]
110. 110. 

     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]
111. 111. 

     Sai K, Parsons C, House JS, Kathariou S, Ninomiya-Tsuji J 2019. Necroptosis mediators RIPK3 and MLKL suppress intracellular Listeria replication independently of host cell killing. J. Cell Biol. 218:1994–2005
     [Google Scholar]
112. 112. 

     Pena SV, Hanson DA, Carr BA, Goralski TJ, Krensky AM 1997. Processing, subcellular localization, and function of 519 (granulysin), a human late T cell activation molecule with homology to small, lytic, granule proteins. J. Immunol. 158:2680–88
     [Google Scholar]
113. 113. 

     Stenger S, Hanson DA, Teitelbaum R, Dewan P, Niazi KR et al. 1998. An antimicrobial activity of cytolytic T cells mediated by granulysin. Science 282:121–25
     [Google Scholar]
114. 114. 

     Chung WH, Hung SI, Yang JY, Su SC, Huang SP et al. 2008. Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis. Nat. Med. 14:1343–50
     [Google Scholar]
115. 115. 

     Veljkovic Vujaklija D, Dominovic M, Gulic T, Mahmutefendic H, Haller H et al. 2013. Granulysin expression and the interplay of granulysin and perforin at the maternal-fetal interface. J. Reprod. Immunol. 97:186–96
     [Google Scholar]
116. 116. 

     Maeda Y, Tamura T, Fukutomi Y, Mukai T, Kai M, Makino M 2011. A lipopeptide facilitate induction of Mycobacterium leprae killing in host cells. PLOS Negl. Trop. Dis. 5:e1401
     [Google Scholar]
117. 117. 

     Leippe M, Ebel S, Schoenberger OL, Horstmann RD, Muller-Eberhard HJ 1991. Pore-forming peptide of pathogenic Entamoeba histolytica. . PNAS 88:7659–63
     [Google Scholar]
118. 118. 

     Hecht O, Van Nuland NA, Schleinkofer K, Dingley AJ, Bruhn H et al. 2004. Solution structure of the pore-forming protein of Entamoeba histolytica. J. Biol. Chem 279:17834–41
     [Google Scholar]
119. 119. 

     Barman H, Walch M, Latinovic-Golic S, Dumrese C, Dolder M et al. 2006. Cholesterol in negatively charged lipid bilayers modulates the effect of the antimicrobial protein granulysin. J. Membr. Biol. 212:29–39
     [Google Scholar]
120. 120. 

     Abe R, Yoshioka N, Murata J, Fujita Y, Shimizu H 2009. Granulysin as a marker for early diagnosis of the Stevens-Johnson syndrome. Ann. Intern. Med. 151:514–15
     [Google Scholar]
121. 121. 

     Dotiwala F, Mulik S, Polidoro RB, Ansara JA, Burleigh BA et al. 2016. Killer lymphocytes use granulysin, perforin and granzymes to kill intracellular parasites. Nat. Med. 22:210–16
     [Google Scholar]
122. 122. 

     Walch M, Dotiwala F, Mulik S, Thiery J, Kirchhausen T et al. 2014. Cytotoxic cells kill intracellular bacteria through granulysin-mediated delivery of granzymes. Cell 157:1309–23
     [Google Scholar]
123. 123. 

     Dotiwala F, Sen Santara S, Binker-Cosen AA, Li B, Chandrasekaran S, Lieberman J 2017. Granzyme B disrupts central metabolism and protein synthesis in bacteria to promote an immune cell death program. Cell 171:1125–37.e11
     [Google Scholar]
124. 124. 

     Li SS, Kyei SK, Timm-McCann M, Ogbomo H, Jones GJ et al. 2013. The NK receptor NKp30 mediates direct fungal recognition and killing and is diminished in NK cells from HIV-infected patients. Cell Host Microbe 14:387–97
     [Google Scholar]
125. 125. 

     Vitenshtein A, Charpak-Amikam Y, Yamin R, Bauman Y, Isaacson B et al. 2016. NK cell recognition of Candida glabrata through binding of NKp46 and NCR1 to fungal ligands Epa1, Epa6, and Epa7. Cell Host Microbe 20:527–34
     [Google Scholar]
126. 126. 

     Huang LP, Lyu SC, Clayberger C, Krensky AM 2007. Granulysin-mediated tumor rejection in transgenic mice. J. Immunol. 178:77–84
     [Google Scholar]
127. 127. 

     Chen X, He WT, Hu L, Li J, Fang Y et al. 2016. Pyroptosis is driven by non-selective gasdermin-D pore and its morphology is different from MLKL channel-mediated necroptosis. Cell Res 26:1007–20
     [Google Scholar]
128. 128. 

     Zhang Y, Chen X, Gueydan C, Han J 2018. Plasma membrane changes during programmed cell deaths. Cell Res 28:9–21
     [Google Scholar]
129. 129. 

     Newton K, Manning G. 2016. Necroptosis and inflammation. Annu. Rev. Biochem. 85:743–63
     [Google Scholar]
130. 130. 

     Davis MA, Fairgrieve MR, Den Hartigh A, Yakovenko O, Duvvuri B et al. 2019. Calpain drives pyroptotic vimentin cleavage, intermediate filament loss, and cell rupture that mediates immunostimulation. PNAS 116:5061–70
     [Google Scholar]
131. 131. 

     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]
132. 132. 

     Hu J, Liu X, Zhao J, Xia S, Ruan J et al. 2018. Identification of pyroptosis inhibitors that target a reactive cysteine in gasdermin D. bioRxiv 365908. https://doi.org/10.1101/365908
     [Crossref]
133. 133. 

     Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A, Nagata S 1998. A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 391:43–50
     [Google Scholar]
134. 134. 

     Thomas DA, Du C, Xu M, Wang X, Ley TJ 2000. DFF45/ICAD can be directly processed by granzyme B during the induction of apoptosis. Immunity 12:621–32
     [Google Scholar]
135. 135. 

     Fan Z, Beresford PJ, Oh DY, Zhang D, Lieberman J 2003. Tumor suppressor NM23-H1 is a granzyme A-activated DNase during CTL-mediated apoptosis, and the nucleosome assembly protein SET is its inhibitor. Cell 112:659–72
     [Google Scholar]
136. 136. 

     Chowdhury D, Beresford PJ, Zhu P, Zhang D, Sung JS et al. 2006. The exonuclease TREX1 is in the SET complex and acts in concert with NM23-H1 to degrade DNA during granzyme A-mediated cell death. Mol. Cell 23:133–42
     [Google Scholar]
137. 136a. 

     Shlomovitz I, Speir M, Gerlic M 2019. Flipping the dogma—phosphatidylserine in non-apoptotic cell death. Cell Commun. Signal 17:139
     [Google Scholar]
138. 136b. 

     Yang X, Cheng X, Tang Y, Qiu X, Wang Y 2019. Bacterial endotoxin activates the coagulation cascade through gasdermin D-dependent phosphatidylserine exposure. Immunity 51:983–96
     [Google Scholar]
139. 137. 

     Nagata S. 2018. Apoptosis and clearance of apoptotic cells. Annu. Rev. Immunol. 36:489–517
     [Google Scholar]
140. 138. 

     Werfel TA, Cook RS. 2018. Efferocytosis in the tumor microenvironment. Semin. Immunopathol. 40:545–54
     [Google Scholar]
141. 139. 

     Poon IK, Lucas CD, Rossi AG, Ravichandran KS 2014. Apoptotic cell clearance: basic biology and therapeutic potential. Nat. Rev. Immunol. 14:166–80
     [Google Scholar]
142. 140. 

     Lieberman J. 2013. Cell-mediated cytotoxicity. Fundamental Immunology WE Paul 891–909 Philadelphia: Wolters Kluwer/Lippincott Williams Wilkins
     [Google Scholar]
143. 141. 

     Kono H, Rock KL. 2008. How dying cells alert the immune system to danger. Nat. Rev. Immunol. 8:279–89
     [Google Scholar]
144. 142. 

     Rus H, Cudrici C, Niculescu F 2005. The role of the complement system in innate immunity. Immunol. Res. 33:103–12
     [Google Scholar]
145. 143. 

     Kjaer TR, Thiel S, Andersen GR 2013. Toward a structure-based comprehension of the lectin pathway of complement. Mol. Immunol. 56:413–22
     [Google Scholar]
146. 144. 

     Uellner R, Zvelebil MJ, Hopkins J, Jones J, MacDougall LK et al. 1997. Perforin is activated by a proteolytic cleavage during biosynthesis which reveals a phospholipid-binding C2 domain. EMBO J 16:7287–96
     [Google Scholar]
147. 145. 

     Dupuis M, Schaerer E, Krause KH, Tschopp J 1993. The calcium-binding protein calreticulin is a major constituent of lytic granules in cytolytic T lymphocytes. J. Exp. Med. 177:1–7
     [Google Scholar]
148. 146. 

     Sula Karreci E, Eskandari SK, Dotiwala F, Routray SK, Kurdi AT et al. 2017. Human regulatory T cells undergo self-inflicted damage via granzyme pathways upon activation. JCI Insight 2:91599
     [Google Scholar]
149. 147. 

     Aglietti RA, Estevez A, Gupta A, Ramirez MG, Liu PS et al. 2016. GsdmD p30 elicited by caspase-11 during pyroptosis forms pores in membranes. PNAS 113:7858–63
     [Google Scholar]
150. 148. 

     Sborgi L, Ruhl S, Mulvihill E, Pipercevic J, Heilig R et al. 2016. GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death. EMBO J 35:1766–78
     [Google Scholar]
151. 149. 

     van Pee K, Mulvihill E, Muller DJ, Yildiz O 2016. Unraveling the pore-forming steps of pneumolysin from Streptococcus pneumoniae. . Nano Lett 16:7915–24
     [Google Scholar]
152. 150. 

     van Pee K, Neuhaus A, D'Imprima E, Mills DJ, Kuhlbrandt W, Yildiz O 2017. CryoEM structures of membrane pore and prepore complex reveal cytolytic mechanism of Pneumolysin. eLife 6:e23644
     [Google Scholar]
153. 151. 

     Liu S, Liu H, Johnston A, Hanna-Addams S, Reynoso E et al. 2017. MLKL forms disulfide bond-dependent amyloid-like polymers to induce necroptosis. PNAS 114:E7450–59
     [Google Scholar]
154. 152. 

     Karch J, Kanisicak O, Brody MJ, Sargent MA, Michael DM, Molkentin JD 2015. Necroptosis interfaces with MOMP and the MPTP in mediating cell death. PLOS ONE 10:e0130520
     [Google Scholar]
155. 153. 

     Rogers C, Erkes DA, Nardone A, Aplin AE, Fernandes-Alnemri T, Alnemri ES 2019. Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation. Nat. Commun. 10:1689
     [Google Scholar]
156. 154. 

     de Vasconcelos NM, Van Opdenbosch N, Van Gorp H, Parthoens E, Lamkanfi M 2019. Single-cell analysis of pyroptosis dynamics reveals conserved GSDMD-mediated subcellular events that precede plasma membrane rupture. Cell Death Differ 26:146–61
     [Google Scholar]
157. 155. 

     Liu J, Qian C, Cao X 2016. Post-translational modification control of innate immunity. Immunity 45:15–30
     [Google Scholar]
158. 156. 

     Liu X, Wang Q, Chen W, Wang C 2013. Dynamic regulation of innate immunity by ubiquitin and ubiquitin-like proteins. Cytokine Growth Factor Rev 24:559–70
     [Google Scholar]
159. 157. 

     Rathkey JK, Zhao J, Liu Z, Chen Y, Yang J et al. 2018. Chemical disruption of the pyroptotic pore-forming protein gasdermin D inhibits inflammatory cell death and sepsis. Sci. Immunol. 3:eaat2738
     [Google Scholar]
160. 158. 

     Kimberley FC, Sivasankar B, Morgan BP 2007. Alternative roles for CD59. Mol. Immunol. 44:73–81
     [Google Scholar]
161. 159. 

     Kim DD, Song WC. 2006. Membrane complement regulatory proteins. Clin. Immunol. 118:127–36
     [Google Scholar]
162. 160. 

     Brodsky RA. 2015. Complement in hemolytic anemia. Blood 126:2459–65
     [Google Scholar]
163. 161. 

     Blink EJ, Trapani JA, Jans DA 1999. Perforin-dependent nuclear targeting of granzymes: a central role in the nuclear events of granule-exocytosis-mediated apoptosis. ? Immunol. Cell Biol. 77:206–15
     [Google Scholar]
164. 162. 

     Martinvalet D, Dykxhoorn DM, Ferrini R, Lieberman J 2008. Granzyme A cleaves a mitochondrial complex I protein to initiate caspase-independent cell death. Cell 133:681–92
     [Google Scholar]
165. 163. 

     Spicer BA, Law RHP, Caradoc-Davies TT, Ekkel SM, Bayly-Jones C et al. 2018. The first transmembrane region of complement component-9 acts as a brake on its self-assembly. Nat. Commun. 9:3266
     [Google Scholar]
166. 164. 

     Huang D, Zheng X, Wang ZA, Chen X, He WT et al. 2017. The MLKL channel in necroptosis is an octamer formed by tetramers in a dyadic process. Mol. Cell. Biol. 37:e00497–16
     [Google Scholar]
167. 165. 

     Xia B, Fang S, Chen X, Hu H, Chen P et al. 2016. MLKL forms cation channels. Cell Res 26:517–28
     [Google Scholar]
168. 166. 

     Tschopp J, Engel A, Podack ER 1984. Molecular weight of poly(C9): 12 to 18 C9 molecules form the transmembrane channel of complement. J. Biol. Chem. 259:1922–28
     [Google Scholar]
169. 167. 

     Liu Z, Wang C, Yang J, Zhou B, Yang R et al. 2019. Crystal structures of the full-length murine and human gasdermin D reveal mechanisms of autoinhibition, lipid binding, and oligomerization. Immunity 51:43–49.e4
     [Google Scholar]
170. 168. 

     Andrews NW, Corrotte M. 2018. Plasma membrane repair. Curr. Biol. 28:R392–97
     [Google Scholar]
171. 169. 

     McNeil PL, Kirchhausen T. 2005. An emergency response team for membrane repair. Nat. Rev. Mol. Cell Biol. 6:499–505
     [Google Scholar]
172. 170. 

     Dal Peraro M, van der Goot FG 2016. Pore-forming toxins: ancient, but never really out of fashion. Nat. Rev. Microbiol. 14:77–92
     [Google Scholar]
173. 171. 

     Tegla CA, Cudrici C, Patel S, Trippe R 3rd, Rus V et al. 2011. Membrane attack by complement: the assembly and biology of terminal complement complexes. Immunol. Res. 51:45–60
     [Google Scholar]
174. 172. 

     Ruhl S, Shkarina K, Demarco B, Heilig R, Santos JC, Broz P 2018. ESCRT-dependent membrane repair negatively regulates pyroptosis downstream of GSDMD activation. Science 362:956–60
     [Google Scholar]
175. 173. 

     Gong YN, Guy C, Olauson H, Becker JU, Yang M et al. 2017. ESCRT-III acts downstream of MLKL to regulate necroptotic cell death and its consequences. Cell 169:286–300.e16
     [Google Scholar]
176. 174. 

     Lieberman J, Wu H, Kagan JC 2019. Gasdermin D activity in inflammation and host defense. Sci. Immunol. 4:eaav1447
     [Google Scholar]
177. 175. 

     Chen KW, Gross CJ, Sotomayor FV, Stacey KJ, Tschopp J et al. 2014. The neutrophil NLRC4 inflammasome selectively promotes IL-1β maturation without pyroptosis during acute Salmonella challenge. Cell Rep 8:570–82
     [Google Scholar]
178. 176. 

     Gaidt MM, Ebert TS, Chauhan D, Schmidt T, Schmid-Burgk JL et al. 2016. Human monocytes engage an alternative inflammasome pathway. Immunity 44:833–46
     [Google Scholar]
179. 177. 

     Wolf AJ, Reyes CN, Liang W, Becker C, Shimada K et al. 2016. Hexokinase is an innate immune receptor for the detection of bacterial peptidoglycan. Cell 166:624–36
     [Google Scholar]
180. 178. 

     Zanoni I, Tan Y, Di Gioia M, Broggi A, Ruan J et al. 2016. An endogenous caspase-11 ligand elicits interleukin-1 release from living dendritic cells. Science 352:1232–36
     [Google Scholar]