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Structural Immunology pp 189–205Cite as

Structural Insight of Gasdermin Family Driving Pyroptotic Cell Death

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Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1172))

Abstract

Gasdermin is a recently identified family of pore-forming proteins consisting of Gasdermin A (GSDMA), Gasdermin B (GSDMB), Gasdermin C (GSDMC), Gasdermin D (GSDMD), Gasdermin E (GSDME), and DFNB59. Gasdermin D (GSDMD) is a downstream effector of inflammasomes, which are supramolecular complexes that activate inflammatory caspases (-1, -4, and -5 in human and -1 and -11 in mouse). GSDMD contains a functionally important N-terminal domain (GSDMD-N), a C-terminal domain, and a linker in between that is recognized and cleaved by the activated inflammatory caspases. Upon cleavage, the GSDMD-N fragments translocate on the membrane and oligomerize to form membrane-embedded pores after specifically binding to acidic lipids such as phosphatidylinositol phosphates (PIPs), phosphatidic acid (PA), phosphatidylserine (PS), and cardiolipin. The pore exhibits strong membrane-disrupting cytotoxicity in mammalian cells by disrupting the osmotic potential and also serves as a gate for extracellular release of mature IL-1β and IL-18 during pyroptosis. In this chapter, we review our current understanding of GSDM proteins in physiological and pathological cell death, with more focused discussions on its structural basis for GSDM activation and pore formation.

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References

  1. Bergsbaken T, Fink SL, Cookson BT (2009) Pyroptosis: host cell death and inflammation. Nat Rev Microbiol 7:99–109. https://doi.org/10.1038/nrmicro2070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Zhang Y, Chen X, Gueydan C, Han J (2018) Plasma membrane changes during programmed cell deaths. Cell Res 28:9–21. https://doi.org/10.1038/cr.2017.133

    Article  CAS  PubMed  Google Scholar 

  3. Martinon F, Burns K, Tschopp J (2002) The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 10:417–426

    Article  CAS  PubMed  Google Scholar 

  4. Man SM, Karki R, Kanneganti TD (2017) Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases. Immunol Rev 277:61–75. https://doi.org/10.1111/imr.12534

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sharma D, Kanneganti TD (2016) The cell biology of inflammasomes: mechanisms of inflammasome activation and regulation. J Cell Biol 213:617–629. https://doi.org/10.1083/jcb.201602089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Broz P, Dixit VM (2016) Inflammasomes: mechanism of assembly, regulation and signalling. Nat Rev Immunol 16:407–420. https://doi.org/10.1038/nri.2016.58

    Article  CAS  PubMed  Google Scholar 

  7. Lu A et al (2014) Unified polymerization mechanism for the assembly of ASC-dependent inflammasomes. Cell 156:1193–1206. https://doi.org/10.1016/j.cell.2014.02.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhang L et al (2015) Cryo-EM structure of the activated NAIP2-NLRC4 inflammasome reveals nucleated polymerization. Science 350:404–409. https://doi.org/10.1126/science.aac5789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hu ZH et al (2015) Structural and biochemical basis for induced self-propagation of NLRC4. Science 350:399–404. https://doi.org/10.1126/science.aac5489

    Article  CAS  PubMed  Google Scholar 

  10. Man SM, Kanneganti TD (2016) Converging roles of caspases in inflammasome activation, cell death and innate immunity. Nat Rev Immunol 16:7–21. https://doi.org/10.1038/nri.2015.7

    Article  CAS  PubMed  Google Scholar 

  11. Howard AD et al (1991) Il-1-converting enzyme requires aspartic-acid residues for processing of the Il-1-beta precursor at 2 distinct sites and does not cleave 31-Kda Il-1-alpha. J Immunol 147:2964–2969

    CAS  PubMed  Google Scholar 

  12. Thornberry NA et al (1992) A novel heterodimeric cysteine protease is required for interleukin-1-beta processing in monocytes. Nature 356:768–774. https://doi.org/10.1038/356768a0

    Article  CAS  PubMed  Google Scholar 

  13. Delaleu N, Bickel M (2004) Interleukin-1 beta and interleukin-18: regulation and activity in local inflammation. Periodontol 2000(35):42–52. https://doi.org/10.1111/j.0906-6713.2004.003569.x

    Article  Google Scholar 

  14. Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H (2001) Interleukin-18 regulates both TH1 and TH2 responses. Annu Rev Immunol 19:423–474. https://doi.org/10.1146/annurev.immunol.19.1.423

    Article  CAS  PubMed  Google Scholar 

  15. Taabazuing CY, Okondo MC, Bachovchin DA (2017) Pyroptosis and apoptosis pathways engage in bidirectional crosstalk in monocytes and macrophages. Cell Chem Biol 24:507–514 e504. https://doi.org/10.1016/j.chembiol.2017.03.009

    Article  PubMed  PubMed Central  Google Scholar 

  16. Shi J, Gao W, Shao F (2017) Pyroptosis: gasdermin-mediated programmed necrotic cell death. Trends Biochem Sci 42:245–254. https://doi.org/10.1016/j.tibs.2016.10.004

    Article  CAS  PubMed  Google Scholar 

  17. Kayagaki N et al (2015) Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526:666–671. https://doi.org/10.1038/nature15541

    Article  CAS  PubMed  Google Scholar 

  18. Hagar JA, Powell DA, Aachoui Y, Ernst RK, Miao EA (2013) Cytoplasmic LPS activates caspase-11: implications in TLR4-independent endotoxic shock. Science 341:1250–1253. https://doi.org/10.1126/science.1240988

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Shi J et al (2014) Inflammatory caspases are innate immune receptors for intracellular LPS. Nature 514:187–192. https://doi.org/10.1038/nature13683

    Article  CAS  PubMed  Google Scholar 

  20. He WT et al (2015) Gasdermin D is an executor of pyroptosis and required for interleukin-1 beta secretion. Cell Res 25:1285–1298. https://doi.org/10.1038/cr.2015.139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kayagaki N et al (2013) Noncanonical inflammasome activation by intracellular LPS independent of TLR4. Science 341:1246–1249. https://doi.org/10.1126/science.1240248

    Article  CAS  PubMed  Google Scholar 

  22. Shi J et al (2015) Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526:660–665. https://doi.org/10.1038/nature15514

    Article  CAS  PubMed  Google Scholar 

  23. Yang J et al (2018) Mechanism of gasdermin D recognition by inflammatory caspases and their inhibition by a gasdermin D-derived peptide inhibitor. Proc Natl Acad Sci USA 115:6792–6797. https://doi.org/10.1073/pnas.1800562115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Liu X et al (2016) Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 535:153–158. https://doi.org/10.1038/nature18629

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ding J et al (2016) Pore-forming activity and structural autoinhibition of the gasdermin family. Nature 535:111–116. https://doi.org/10.1038/nature18590

    Article  CAS  PubMed  Google Scholar 

  26. Chen X et al (2016) Pyroptosis is driven by non-selective gasdermin-D pore and its morphology is different from MLKL channel-mediated necroptosis. Cell Res 26:1007–1020. https://doi.org/10.1038/cr.2016.100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. de Vasconcelos NM, Van Opdenbosch N, Van Gorp H, Parthoens E, Lamkanfi M (2018) Single-cell analysis of pyroptosis dynamics reveals conserved GSDMD-mediated subcellular events that precede plasma membrane rupture. Cell Death Differ. https://doi.org/10.1038/s41418-018-0106-7

    Article  PubMed  PubMed Central  Google Scholar 

  28. Sborgi L et al (2016) GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death. EMBO J 35:1766–1778. https://doi.org/10.15252/embj.201694696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gaidt MM, Hornung V (2016) Pore formation by GSDMD is the effector mechanism of pyroptosis. EMBO J 35:2167–2169. https://doi.org/10.15252/embj.201695415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lei XB et al (2017) Enterovirus 71 inhibits pyroptosis through cleavage of gasdermin D. J Virol 91. UNSP e01069-1710.1128/JVI.01069-17

    Google Scholar 

  31. Okondo MC et al (2017) DPP8 and DPP9 inhibition induces pro-caspase-1-dependent monocyte and macrophage pyroptosis. Nat Chem Biol 13:46–53. https://doi.org/10.1038/nchembio.2229

    Article  CAS  PubMed  Google Scholar 

  32. Brinkmann V et al (2004) Neutrophil extracellular traps kill bacteria. Science 303:1532–1535. https://doi.org/10.1126/science.1092385

    Article  CAS  PubMed  Google Scholar 

  33. Fuchs TA et al (2007) Novel cell death program leads to neutrophil extracellular traps. J Cell Biol 176:231–241. https://doi.org/10.1083/jcb.200606027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Urban CF et al (2009) Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans. PLoS Pathog 5:e1000639. https://doi.org/10.1371/journal.ppat.1000639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. McDonald B, Urrutia R, Yipp BG, Jenne CN, Kubes P (2012) Intravascular neutrophil extracellular traps capture bacteria from the bloodstream during sepsis. Cell Host Microbe 12:324–333. https://doi.org/10.1016/j.chom.2012.06.011

    Article  CAS  PubMed  Google Scholar 

  36. Sollberger G et al (2018) Gasdermin D plays a vital role in the generation of neutrophil extracellular traps. Sci Immunol 3. https://doi.org/10.1126/sciimmunol.aar6689

    Article  PubMed  Google Scholar 

  37. Chen KW et al (2018) Noncanonical inflammasome signaling elicits gasdermin D-dependent neutrophil extracellular traps. Sci Immunol 3. https://doi.org/10.1126/sciimmunol.aar6676

    Article  PubMed  Google Scholar 

  38. Kambara H et al (2018) Gasdermin D exerts anti-inflammatory effects by promoting neutrophil death. Cell Rep 22:2924–2936. https://doi.org/10.1016/j.celrep.2018.02.067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Tamura M 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 89:618–629. https://doi.org/10.1016/j.ygeno.2007.01.003

    Article  CAS  PubMed  Google Scholar 

  40. Van Laer L et al (1998) Nonsyndromic hearing impairment is associated with a mutation in DFNA5. Nat Genet 20:194–197

    Article  PubMed  Google Scholar 

  41. Delmaghani S et al (2006) Mutations in the gene encoding pejvakin, a newly identified protein of the afferent auditory pathway, cause DFNB59 auditory neuropathy. Nat Genet 38:770–778. https://doi.org/10.1038/ng1829

    Article  CAS  PubMed  Google Scholar 

  42. Saeki N, Sasaki H (2012) Gasdermin superfamily: a novel gene family functioning in epithelial cells. In: Carrasco J, Mota M (eds) Endothelium and epithelium. Nova Science Publishers, pp 193–211

    Google Scholar 

  43. Tanaka S, Mizushina Y, Kato Y, Tamura M, Shiroishi T (2013) Functional conservation of Gsdma cluster genes specifically duplicated in the mouse genome. G3-Genes Genom Genet 3:1843–1850. https://doi.org/10.1534/g3.113.007393

    Article  PubMed  PubMed Central  Google Scholar 

  44. Ruan J, Xia S, Liu X, Lieberman J, Wu H (2018) Cryo-EM structure of the gasdermin A3 membrane pore. Nature 557:62–67. https://doi.org/10.1038/s41586-018-0058-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wang YP et al (2017) Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature 547:99–+. https://doi.org/10.1038/nature22393

    Article  CAS  PubMed  Google Scholar 

  46. Liu Z et al (2018) Structures of the gasdermin D C-terminal domains reveal mechanisms of autoinhibition. Structure 26:778–784 e773. https://doi.org/10.1016/j.str.2018.03.002

    Article  PubMed  PubMed Central  Google Scholar 

  47. Kuang SY et al (2017) Structure insight of GSDMD reveals the basis of GSDMD autoinhibition in cell pyroptosis. P Natl Acad Sci USA 114:10642–10647. https://doi.org/10.1073/pnas.1708194114

    Article  CAS  Google Scholar 

  48. 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. Proc Natl Acad Sci USA 114:E1128–E1137. https://doi.org/10.1073/pnas.1616783114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lin PH, Lin HY, Kuo CC, Yang LT (2015) N-terminal functional domain of Gasdermin A3 regulates mitochondrial homeostasis via mitochondrial targeting. J Biomed Sci 22. https://doi.org/10.1186/s12929-015-0152-0

  50. Rathkey JK et al (2017) Live-cell visualization of gasdermin D-driven pyroptotic cell death. J Biol Chem 292:14649–14658. https://doi.org/10.1074/jbc.M117.797217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Mulvihill E et al (2018) Mechanism of membrane pore formation by human gasdermin-D. Embo J 37. https://doi.org/10.15252/embj.201798321

  52. Aglietti RA et al (2016) GsdmD p30 elicited by caspase-11 during pyroptosis forms pores in membranes. Proc Natl Acad Sci USA 113:7858–7863. https://doi.org/10.1073/pnas.1607769113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Dal Peraro M, van der Goot FG (2016) Pore-forming toxins: ancient, but never really out of fashion. Nat Rev Microbiol 14:77–92. https://doi.org/10.1038/nrmicro.2015.3

    Article  CAS  Google Scholar 

  54. Wade KR et al (2015) An intermolecular electrostatic interaction controls the prepore-to-pore transition in a cholesterol-dependent cytolysin. Proc Natl Acad Sci USA 112:2204–2209. https://doi.org/10.1073/pnas.1423754112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Yamashita D et al (2014) Molecular basis of transmembrane beta-barrel formation of staphylococcal pore-forming toxins. Nat Commun 5. ARTN 489710.1038/ncomms5897

    Google Scholar 

  56. Degiacomi MT et al (2013) Molecular assembly of the aerolysin pore reveals a swirling membrane-insertion mechanism. Nat Chem Biol 9:623–629. https://doi.org/10.1038/Nchembio.1312

    Article  CAS  PubMed  Google Scholar 

  57. van Pee K et al (2017) CryoEM structures of membrane pore and prepore complex reveal cytolytic mechanism of Pneumolysin. Elife 6. ARTN e2364410.7554/eLife.23644

    Google Scholar 

  58. Kovacs SB, Miao EA (2017) Gasdermins: effectors of pyroptosis. Trends Cell Biol 27:673–684. https://doi.org/10.1016/j.tcb.2017.05.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Saeki N, Kuwahara Y, Sasaki H, Satoh H, Shiroishi T (2000) Gasdermin (Gsdm) localizing to mouse Chromosome 11 is predominantly expressed in upper gastrointestinal tract bud significantly suppressed in human gastric cancer cells. Mamm Genome 11:718–724. https://doi.org/10.1007/s003350010138

    Article  CAS  PubMed  Google Scholar 

  60. Saeki N et al (2007) GASDERMIN, suppressed frequently in gastric cancer, is a target of LMO1 in TGF-beta-dependent apoptotic signalling. Oncogene 26:6488–6498. https://doi.org/10.1038/sj.onc.1210475

    Article  CAS  PubMed  Google Scholar 

  61. Saeki N et al (2009) Distinctive expression and function of four GSDM family genes (GSDMA-D) in normal and malignant upper gastrointestinal epithelium. Genes Chromosomes Cancer 48:261–271. https://doi.org/10.1002/gcc.20636

    Article  CAS  PubMed  Google Scholar 

  62. Das S et al (2016) GSDMB induces an asthma phenotype characterized by increased airway responsiveness and remodeling without lung inflammation. Proc Natl Acad Sci USA 113:13132–13137. https://doi.org/10.1073/pnas.1610433113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Wu H et al (2009) Genetic variation in ORM1-like 3 (ORMDL3) and gasdermin-like (GSDML) and childhood asthma. Allergy 64:629–635. https://doi.org/10.1111/j.1398-9995.2008.01912.x

    Article  CAS  PubMed  Google Scholar 

  64. Hergueta-Redondo M et al (2014) Gasdermin-B promotes invasion and metastasis in breast cancer cells. Plos One 9. ARTN e9009910.1371/journal.pone.0090099

    Article  PubMed  PubMed Central  Google Scholar 

  65. Hergueta-Redondo M et al (2016) Gasdermin B expression predicts poor clinical outcome in HER2-positive breast cancer. Oncotarget 7:56295–56308. https://doi.org/10.18632/oncotarget.10787

    Article  PubMed  PubMed Central  Google Scholar 

  66. Watabe K et al (2001) Structure, expression and chromosome mapping of MLZE, a novel gene which is preferentially expressed in metastatic melanoma cells. Jpn J Cancer Res 92:140–151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Wu C et al (2009) BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources. Genome Biol 10:R130. https://doi.org/10.1186/gb-2009-10-11-r130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Masuda Y et al (2006) The potential role of DFNA5, a hearing impairment gene, in p53-mediated cellular response to DNA damage. J Hum Genet 51:652–664. https://doi.org/10.1007/s10038-006-0004-6

    Article  CAS  PubMed  Google Scholar 

  69. Liu W, Kinnefors A, Bostrom M, Edin F, Rask-Andersen H (2013) Distribution of pejvakin in human spiral ganglion: an immunohistochemical study. Cochlear Implants Int 14:225–231. https://doi.org/10.1179/1754762812Y.0000000027

    Article  PubMed  Google Scholar 

  70. Dereeper A et al (2008) Phylogeny.fr: robust phylogenetic analysis for the non-specialist. Nucleic Acids Res 36:W465–469. https://doi.org/10.1093/nar/gkn180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Dereeper A, Audic S, Claverie JM, Blanc G (2010) BLAST-EXPLORER helps you building datasets for phylogenetic analysis. BMC Evol Biol 10:8. https://doi.org/10.1186/1471-2148-10-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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The author declares that there are no conflicts of interest related to this study.

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Authors and Affiliations

  1. Department of Immunology, University of Connecticut Health Center, Farmington, CT, USA

    Jianbin Ruan

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  1. Jianbin Ruan
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Correspondence to Jianbin Ruan .

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Editors and Affiliations

  1. The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China

    Tengchuan Jin

  2. Department of Biological Science, Florida State University, Tallahassee, FL, USA

    Qian Yin

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Ruan, J. (2019). Structural Insight of Gasdermin Family Driving Pyroptotic Cell Death. In: Jin, T., Yin, Q. (eds) Structural Immunology. Advances in Experimental Medicine and Biology, vol 1172. Springer, Singapore. https://doi.org/10.1007/978-981-13-9367-9_9

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