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Cited by 74Inflammasome and immune disordersCell death mechanisms and regulationImmune Response and Inflammation

Regulation of Lytic and Non-Lytic Functions of Gasdermin Pores

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Rühl, Sebastian, Broz, Petr·2022·Journal of Molecular Biology
DOI 10.1016/j.jmb.2021.167246
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Abstract

Pyroptosis is a necrotic form of cell death that was initially found to be induced upon activation of inflammatory caspases by inflammasome complexes. Mechanistically, pyroptosis induction requires cleavage of the caspase substrate gasdermin D (GSDMD), and the release of the GSDMD N-terminal fragment, which targets the plasma membrane to form large β-barrel pores. GSDMD shares this pore-forming ability with other gasdermin family members, which induce pyroptosis during infection or upon treatment with chemotherapy drugs. While induction of cell death has been assumed to be the main function of the gasdermin pores, increasing evidence suggests that these pores have non-lytic functions, such as in releasing cytokines or alarmins and in regulating intracellular signaling via ionic fluxes. Here we discuss how gasdermin pore formation is regulated to induce membrane permeabilization or lysis, how gasdermin pores achieve specificity for cargo-release and how cells repair gasdermin-induced damage to the plasma membrane.

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  • Pyroptosis may occur downstream of GSDMD pore formation and is mediated by Ninjurin1, a cell surface protein that induces plasma membrane rupture upon its oligomerization.

    “Pyroptosis may occur downstream of GSDMD pore formation and is mediated by Ninjurin1 (NINJ1), a cell surface protein that induces plasma membrane rupture upon its oligomerization [68, 69].”

    From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [68]

    The section on pyroptotic cell lysis (page unavailable) places NINJ1-mediated plasma membrane rupture downstream of GSDMD pores and says NINJ1 oligomerization is required for rupture. It also distinguishes rupture from other GSDMD-pore functions, including IL-1β secretion. Thus, the paper supports NINJ1’s role in the lytic stage, but not the broader statement that NINJ1 mediates pyroptosis as a whole. (LLM, conf=0.84)

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  1. Zychlinsky, A., Prevost, M.C., Sansonetti, P.J., (1992). Shigella flexneri induces apoptosis in infected macrophages. Nature, 358, 167-169. https://doi.org/ 10.1038/358167a0. · DOI
  2. 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. https://doi.org/ S1097276502005993 [pii].
  3. Broz, P., Dixit, V.M., (2016). Inflammasomes: mechanism of assembly, regulation and signalling. Nature Rev. Immunol., 16, 407-420. https://doi.org/10.1038/ nri.2016.58. · DOI · Paper page
  4. Fink, S.L., Cookson, B.T., (2006). Caspase-1-dependent pore formation during pyroptosis leads to osmotic lysis of infected host macrophages. Cell. Microbiol., 8, 1812- 1825. https://doi.org/10.1111/j.1462-5822.2006.00751.x. · DOI
  5. Kayagaki, N., Stowe, I.B., Lee, B.L., O'Rourke, K., Anderson, K., Warming, S., Cuellar, T., Haley, B., et al., (2015). Caspase-11 cleaves gasdermin D for non- canonical inflammasome signalling. Nature, 526, 666- 671. https://doi.org/10.1038/nature15541. · DOI · Paper page
  6. Shi, J., Zhao, Y., Wang, K., Shi, X., Wang, Y., Huang, H., Zhuang, Y., Cai, T., et al., (2015). Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature, 526, 660-665. https://doi.org/ 10.1038/nature15514. · DOI · Paper page
  7. He, W.T., Wan, H., Hu, L., Chen, P., Wang, X., Huang, Z., Yang, Z.H., Zhong, C.Q., et al., (2015). Gasdermin D is an executor of pyroptosis and required for interleukin-1beta secretion. Cell Res., 25, 1285-1298. https://doi.org/ 10.1038/cr.2015.139. · DOI · Paper page
  8. Sborgi, L., Ruhl, S., Mulvihill, E., Pipercevic, J., Heilig, R., Stahlberg, H., Farady, C.J., Muller, D.J., 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. · DOI · Paper page
  9. Aglietti, R.A., Estevez, A., Gupta, A., Ramirez, M.G., Liu, P.S., Kayagaki, N., Ciferri, C., Dixit, V.M., et al., (2016). GsdmD p30 elicited by caspase-11 during pyroptosis forms pores in membranes. PNAS, 113, 7858-7863. https://doi.org/10.1073/pnas.1607769113. · DOI · Paper page
  10. Liu, X., Zhang, Z., Ruan, J., Pan, Y., Magupalli, V.G., Wu, H., Lieberman, J., (2016). Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature, 535, 153-158. https://doi.org/ 10.1038/nature18629. · DOI · Paper page
  11. Ding, J., Wang, K., Liu, W., She, Y., Sun, Q., Shi, J., Sun, H., Wang, D.C., et al., (2016). Pore-forming activity and structural autoinhibition of the gasdermin family. Nature, 535, 111-116. https://doi.org/10.1038/nature18590. · DOI · Paper page
  12. Monteleone, M., Stow, J.L., Schroder, K., (2015). Mechanisms of unconventional secretion of IL-1 family cytokines. Cytokine, 74, 213-218. https://doi.org/10.1016/ j.cyto.2015.03.022. · DOI
  13. Zhou, Y., Jiang, X., Gu, P., Chen, W., Zeng, X., Gao, X., (2012). Gsdma3 mutation causes bulge stem cell depletion and alopecia mediated by skin inflammation. Am. J. Pathol., 180, 763-774. https://doi.org/10.1016/j. ajpath.2011.10.034. · DOI
  14. Van Rossom, S., Op de Beeck, K., Franssens, V., Swinnen, E., Schepers, A., Ghillebert, R., Caldara, M., Van Camp, G., et al., (2012). The splicing mutant of the human tumor suppressor protein DFNA5 induces programmed cell death when expressed in the yeast Saccharomyces cerevisiae. Front. Oncol., 2, 77. https:// doi.org/10.3389/fonc.2012.00077. · DOI
  15. Op de Beeck, K., Van Camp, G., Thys, S., Cools, N., Callebaut, I., Vrijens, K., Van Nassauw, L., Van Tendeloo, V.F., et al., (2011). The DFNA5 gene, responsible for hearing loss and involved in cancer, encodes a novel apoptosis-inducing protein. Eur. J. Hum. Genet., 19, 965- 973. https://doi.org/10.1038/ejhg.2011.63. · DOI
  16. Van Laer, L., Huizing, E.H., Verstreken, M., van Zuijlen, D., Wauters, J.G., Bossuyt, P.J., Van de Heyning, P., McGuirt, W.T., et al., (1998). Nonsyndromic hearing impairment is associated with a mutation in DFNA5. Nature Genet., 20, 194-197. https://doi.org/10.1038/ 2503. · DOI
  17. Broz, P., (2015). Immunology: Caspase target drives pyroptosis. Nature, 526, 642-643. https://doi.org/ 10.1038/nature15632. · DOI
  18. Sollberger, G., Choidas, A., Burn, G.L., Habenberger, P., Di Lucrezia, R., Kordes, S., Menninger, S., Eickhoff, J., 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. · DOI
  19. Demarco, B., Grayczyk, J.P., Bjanes, E., Le Roy, D., Tonnus, W., Assenmacher, C.-A., Radaelli, E., Fettrelet, T., et al., (2020). Caspase-8-dependent gasdermin D cleavage promotes antimicrobial defense but confers susceptibility to TNF-induced lethality. Sci. Adv., 6 https://doi.org/10.1126/sciadv.abc3465. · DOI
  20. Chen, K.W., Demarco, B., Heilig, R., Shkarina, K., Boettcher, A., Farady, C.J., Pelczar, P., Broz, P., (2019). Extrinsic and intrinsic apoptosis activate pannexin-1 to drive NLRP3 inflammasome assembly. EMBO J.,. https://doi.org/10.15252/embj.2019101638. · DOI
  21. Orning, P., Weng, D., Starheim, K., Ratner, D., Best, Z., Lee, B., Brooks, A., Xia, S., et al., (2018). Pathogen blockade of TAK1 triggers caspase-8-dependent cleavage of gasdermin D and cell death. Science, 362, 1064-1069. https://doi.org/10.1126/science.aau2818. · DOI
  22. Sarhan, J., Liu, B.C., Muendlein, H.I., Li, P., Nilson, R., Tang, A.Y., Rongvaux, A., Bunnell, S.C., et al., (2018). Caspase-8 induces cleavage of gasdermin D to elicit pyroptosis during Yersinia infection. PNAS, 115, E10888- E10897. https://doi.org/10.1073/pnas.1809548115. · DOI
  23. Zhou, Z., He, H., Wang, K., Shi, X., Wang, Y., Su, Y., Wang, Y., Li, D., et al., (2020). Granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells. Science, 368 https://doi.org/10.1126/science. aaz7548. · DOI · Paper page
  24. Zhang, J.-Y., Zhou, B., Sun, R.-Y., Ai, Y.-L., Cheng, K., Li, F.-N., Wang, B.-R., Liu, F.-J., et al., (2021). The metabolite a-KG induces GSDMC-dependent pyroptosis through death receptor 6-activated caspase-8. Cell Res.,. https://doi.org/10.1038/s41422-021-00506-9. · DOI
  25. Hou, J., Zhao, R., Xia, W., Chang, C.-W., You, Y., Hsu, J.- M., Nie, L., Chen, Y., et al., (2020). PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumour necrosis. Nature Cell Biol., 22, 1264-1275. https://doi.org/10.1038/s41556-020- 0575-z. · DOI
  26. Wang, Y., Gao, W., Shi, X., Ding, J., Liu, W., He, H., Wang, K., Shao, F., (2017). Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature, 547, 99-103. https://doi.org/ 10.1038/nature22393. · DOI · Paper page
  27. Taabazuing, C.Y., Okondo, M.C., Bachovchin, D.A., (2017). Pyroptosis and apoptosis pathways engage in bidirectional crosstalk in monocytes and macrophages. Cell Chem. Biol., 24, 507-514.e4. https://doi.org/10.1016/ j.chembiol.2017.03.009. · DOI
  28. Zhang, Z., Zhang, Y., Xia, S., Kong, Q., Li, S., Liu, X., Junqueira, C., Meza-Sosa, K.F., et al., (2020). Gasdermin E suppresses tumour growth by activating anti-tumour immunity. Nature, 579, 415-420. https://doi.org/10.1038/ s41586-020-2071-9. · DOI
  29. Rogers, C., Erkes, D.A., Nardone, A., Aplin, A.E., Fernandes-Alnemri, T., Alnemri, E.S., (2019). Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation. Nature Commun., 10, 1689. https://doi.org/ 10.1038/s41467-019-09397-2. · DOI
  30. Wang, Q., Wang, Y., Ding, J., Wang, C., Zhou, X., Gao, W., Huang, H., Shao, F., et al., (2020). A bioorthogonal system reveals antitumour immune function of pyroptosis. Nature, 579, 421-426. https://doi.org/10.1038/s41586- 020-2079-1. · DOI
  31. Erkes, D.A., Cai, W., Sanchez, I.M., Purwin, T.J., Rogers, C., Field, C.O., Berger, A.C., Hartsough, E.J., et al., (2020). Mutant BRAF and MEK Inhibitors Regulate the Tumor Immune Microenvironment via Pyroptosis. Cancer Discov., 10, 254-269. https://doi.org/10.1158/2159-8290. CD-19-0672. · DOI · Paper page
  32. Kim, M.S., Chang, X., Yamashita, K., Nagpal, J.K., Baek, J.H., Wu, G., Trink, B., Ratovitski, E.A., et al., (2008). Aberrant promoter methylation and tumor suppressive activity of the DFNA5 gene in colorectal carcinoma. Oncogene, 27, 3624-3634. https://doi.org/10.1038/sj. onc.1211021. · DOI
  33. Akino, K., Toyota, M., Suzuki, H., Imai, T., Maruyama, R., Kusano, M., Nishikawa, N., Watanabe, Y., et al., (2007). Identification of DFNA5 as a target of epigenetic inactivation in gastric cancer. Cancer Sci., 98, 88-95. https://doi.org/10.1111/j.1349-7006.2006.00351.x. · DOI
  34. Orzalli, M.H., Prochera, A., Payne, L., Smith, A., Garlick, J.A., Kagan, J.C., (2021). Virus-mediated inactivation of anti-apoptotic Bcl-2 family members promotes Gasdermin-E-dependent pyroptosis in barrier epithelial cells. Immunity, 54, 1447-1462.e5. https://doi.org/ 10.1016/j.immuni.2021.04.012. · DOI
  35. Chen, K.W., Demarco, B., Ramos, S., Heilig, R., Goris, M., Grayczyk, J.P., Assenmacher, C.-A., Radaelli, E., et al., (2021). RIPK1 activates distinct gasdermins in macrophages and neutrophils upon pathogen blockade of innate immune signaling. Proc Natl Acad Sci USA, 118, https://doi.org/10.1073/pnas.2101189118 e2101189118. · DOI
  36. Broz, P., Pelegrı ´n, P., Shao, F., (2020). The gasdermins, a protein family executing cell death and inflammation. Nature Rev. Immunol., 20, 143-157. https://doi.org/ 10.1038/s41577-019-0228-2. · DOI · Paper page
  37. Tanaka, S., Mizushina, Y., Kato, Y., Tamura, M., Shiroishi, T., (2013). Functional conservation of Gsdma cluster genes specifically duplicated in the mouse genome. G3 (Bethesda), 3, 1843-1850. https://doi.org/ 10.1534/g3.113.007393. · DOI
  38. Runkel, F., Marquardt, A., Stoeger, C., Kochmann, E., Simon, D., Kohnke, B., Korthaus, D., Wattler, F., et al., (2004). The dominant alopecia phenotypes Bareskin, Rex-denuded, and Reduced Coat 2 are caused by mutations in gasdermin 3. Genomics, 84, 824-835. https://doi.org/10.1016/j.ygeno.2004.07.003. · DOI
  39. Lamkanfi, M., (2011). Emerging inflammasome effector mechanisms. Nature Rev. Immunol., 11, 213-220. https://doi.org/nri2936 [pii] 10.1038/nri2936. · DOI
  40. de Vasconcelos, N.M., 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- 161. https://doi.org/10.1038/s41418-018-0106-7. · DOI
  41. Shkarina, K., Hasel de Carvalho, E., Santos, J.C., Leptin, M., Broz, P., (2021). Optogenetic activators of apoptosis, necroptosis and pyroptosis for probing cell death dynamics and bystander cell responses. Cell Biol.,. https://doi.org/10.1101/2021.08.31.458313. · DOI
  42. Thornberry, N.A., Bull, H.G., Calaycay, J.R., Chapman, K. T., Howard, A.D., Kostura, M.J., Miller, D.K., Molineaux, S.M., 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. · DOI
  43. Gross, O., Yazdi, A.S., Thomas, C.J., Masin, M., Heinz, L. X., Guarda, G., Quadroni, M., Drexler, S.K., et al., (2012). Inflammasome activators induce interleukin-1a secretion via distinct pathways with differential requirement for the protease function of caspase-1. Immunity, 36, 388-400. https://doi.org/10.1016/j.immuni.2012.01.018. · DOI
  44. Kim, J., Gee, H.Y., Lee, M.G., (2018). Unconventional protein secretion -new insights into the pathogenesis and therapeutic targets of human diseases. J. Cell Sci., 131, jcs213686. https://doi.org/10.1242/jcs.213686. · DOI
  45. Zhang, M., Kenny, S.J., Ge, L., Xu, K., Schekman, R., (2015). Translocation of interleukin-1b into a vesicle intermediate in autophagy-mediated secretion. Elife., 4, https://doi.org/10.7554/eLife.11205 e11205. · DOI
  46. Bianco, F., Pravettoni, E., Colombo, A., Schenk, U., Mo ¨ller, T., Matteoli, M., Verderio, C., (2005). Astrocyte- derived ATP induces vesicle shedding and IL-1 beta release from microglia. J. Immunol., 174, 7268-7277. https://doi.org/10.4049/jimmunol.174.11.7268. · DOI · Paper page
  47. Kimura, T., Jia, J., Kumar, S., Choi, S.W., Gu, Y., Mudd, M., Dupont, N., Jiang, S., et al., (2017). Dedicated SNAREs and specialized TRIM cargo receptors mediate secretory autophagy. EMBO J., 36, 42-60. https://doi.org/ 10.15252/embj.201695081. · DOI
  48. Kimura, T., Jia, J., Claude-Taupin, A., Kumar, S., Choi, S. W., Gu, Y., Mudd, M., Dupont, N., et al., (2017). Cellular and molecular mechanism for secretory autophagy. Autophagy., 13, 1084-1085. https://doi.org/10.1080/ 15548627.2017.1307486. · DOI
  49. Jiang, S., Dupont, N., Castillo, E.F., Deretic, V., (2013). Secretory versus degradative autophagy: unconventional secretion of inflammatory mediators. J. Innate Immun., 5, 471-479. https://doi.org/10.1159/000346707. · DOI · Paper page
  50. Brough, D., Rothwell, N.J., (2007). Caspase-1-dependent processing of pro-interleukin-1beta is cytosolic and precedes cell death. J. Cell Sci., 120, 772-781. https:// doi.org/10.1242/jcs.03377. · DOI · Paper page
  51. Martı ´n-Sa ´nchez, F., Diamond, C., Zeitler, M., Gomez, A. I., Baroja-Mazo, A., Bagnall, J., Spiller, D., White, M., et al., (2016). Inflammasome-dependent IL-1b release depends upon membrane permeabilisation. Cell Death Differ., 23, 1219-1231. https://doi.org/10.1038/ cdd.2015.176. · DOI
  52. Shirasaki, Y., Yamagishi, M., Suzuki, N., Izawa, K., Nakahara, A., Mizuno, J., Shoji, S., Heike, T., et al., (2014). Real-time single-cell imaging of protein secretion. Sci. Rep., 4, 4736. https://doi.org/10.1038/srep04736. · DOI
  53. Chen, K.W., Gross, C.J., Sotomayor, F.V., Stacey, K.J., Tschopp, J., Sweet, M.J., Schroder, K., (2014). The neutrophil NLRC4 inflammasome selectively promotes IL- 1beta maturation without pyroptosis during acute Salmonella challenge. Cell Rep., 8, 570-582. https://doi. org/10.1016/j.celrep.2014.06.028. · DOI
  54. Heilig, R., Dick, M.S., Sborgi, L., Meunier, E., Hiller, S., Broz, P., (2018). The Gasdermin-D pore acts as a conduit for IL-1b secretion in mice. Eur. J. Immunol., 48, 584-592. https://doi.org/10.1002/eji.201747404. · DOI
  55. Karmakar, M., Katsnelson, M.A., Dubyak, G.R., Pearlman, E., (2016). Neutrophil P2X7 receptors mediate NLRP3 inflammasome-dependent IL-1beta secretion in response to ATP. Nature Commun., 7, 10555. https://doi.org/10.1038/ncomms10555. · DOI · Paper page
  56. Monteleone, M., Stanley, A.C., Chen, K.W., Brown, D.L., Bezbradica, J.S., von Pein, J.B., Holley, C.L., Boucher, D., et al., (2018). Interleukin-1b Maturation Triggers Its Relocation to the Plasma Membrane for Gasdermin-D- Dependent and -Independent Secretion. Cell Rep., 24, 1425-1433. https://doi.org/10.1016/j.celrep.2018.07.027. · DOI
  57. Zanoni, I., Tan, Y., Di Gioia, M., Broggi, A., Ruan, J., Shi, J., Donado, C.A., Shao, F., et al., (2016). An endogenous caspase-11 ligand elicits interleukin-1 release from living dendritic cells. Science, 352, 1232-1236. https://doi.org/ 10.1126/science.aaf3036. · DOI · Paper page
  58. Evavold, C.L., Ruan, J., Tan, Y., Xia, S., Wu, H., Kagan, J. C., (2018). The Pore-Forming Protein Gasdermin D Regulates Interleukin-1 Secretion from Living Macrophages. Immunity, 48, 35-44.e6. https://doi.org/ 10.1016/j.immuni.2017.11.013. · DOI · Paper page
  59. Zhivaki, D., Borriello, F., Chow, O.A., Doran, B., Fleming, I., Theisen, D.J., Pallis, P., Shalek, A.K., et al., (2020). Inflammasomes within Hyperactive Murine Dendritic Cells Stimulate Long-Lived T Cell-Mediated Anti-tumor Immunity. Cell Rep., 33, https://doi.org/10.1016/j. celrep.2020.108381 108381. · DOI
  60. Wolf, A.J., Reyes, C.N., Liang, W., Becker, C., Shimada, K., Wheeler, M.L., Cho, H.C., Popescu, N.I., et al., (2016). Hexokinase Is an Innate Immune Receptor for the Detection of Bacterial Peptidoglycan. Cell, 166, 624- 636. https://doi.org/10.1016/j.cell.2016.05.076. · DOI
  61. Hara, H., Seregin, S.S., Yang, D., Fukase, K., Chamaillard, M., Alnemri, E.S., Inohara, N., Chen, G.Y., et al., (2018). The NLRP6 Inflammasome Recognizes Lipoteichoic Acid and Regulates Gram-Positive Pathogen Infection. Cell, 175, 1651-1664.e14. https://doi.org/ 10.1016/j.cell.2018.09.047. · DOI
  62. 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. · DOI
  63. Xia, S., Zhang, Z., Magupalli, V.G., Pablo, J.L., Dong, Y., Vora, S.M., Wang, L., Fu, T.-M., et al., (2021). Gasdermin D pore structure reveals preferential release of mature interleukin-1. Nature, 593, 607-611. https://doi.org/ 10.1038/s41586-021-03478-3. · DOI
  64. Ru ¨hl, S., Shkarina, K., Demarco, B., Heilig, R., Santos, J. C., Broz, P., (2018). ESCRT-dependent membrane repair negatively regulates pyroptosis downstream of GSDMD activation. Science, 362, 956-960. https://doi.org/ 10.1126/science.aar7607. · DOI
  65. Chen, X., He, W.T., Hu, L., Li, J., Fang, Y., Wang, X., Xu, X., Wang, Z., 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. · DOI · Paper page
  66. Ru ¨hl, S., Broz, P., (2015). Caspase-11 activates a canonical NLRP3 inflammasome by promoting K(+) efflux. Eur. J. Immunol., 45, 2927-2936. https://doi.org/ 10.1002/eji.201545772. · DOI
  67. Banerjee, I., Behl, B., Mendonca, M., Shrivastava, G., Russo, A.J., Menoret, A., Ghosh, A., Vella, A.T., et al., (2018). Gasdermin D Restrains Type I Interferon Response to Cytosolic DNA by Disrupting Ionic Homeostasis. Immunity, 49, 413-426.e5. https://doi.org/ 10.1016/j.immuni.2018.07.006. · DOI
  68. Kayagaki, N., Lee, B.L., Stowe, I.B., Kornfeld, O.S., O'Rourke, K., Mirrashidi, K.M., Haley, B., Watanabe, C., et al., (2019). IRF2 transcriptionally induces GSDMD expression for pyroptosis. Sci. Signal., 12 https://doi.org/ 10.1126/scisignal.aax4917. · DOI
  69. Benaoudia, S., Martin, A., Puig Gamez, M., Gay, G., Lagrange, B., Cornut, M., Krasnykov, K., Claude, J.-B., et al., (2019). A genome-wide screen identifies IRF2 as a key regulator of caspase-4 in human cells. EMBO Rep., 20, https://doi.org/10.15252/embr.201948235 e48235. · DOI
  70. Humphries, F., Shmuel-Galia, L., Ketelut-Carneiro, N., Li, S., Wang, B., Nemmara, V.V., Wilson, R., Jiang, Z., et al., (2020). Succination inactivates gasdermin D and blocks pyroptosis. Science, 369, 1633-1637. https://doi.org/ 10.1126/science.abb9818. · DOI
  71. Hu, J.J., Liu, X., Xia, S., Zhang, Z., Zhang, Y., Zhao, J., Ruan, J., Luo, X., et al., (2020). FDA-approved disulfiram inhibits pyroptosis by blocking gasdermin D pore formation. Nature Immunol., 21, 736-745. https://doi.org/ 10.1038/s41590-020-0669-6. · DOI · Paper page
  72. Rathkey, J.K., Zhao, J., Liu, Z., Chen, Y., Yang, J., Kondolf, H.C., Benson, B.L., Chirieleison, S.M., et al., (2018). Chemical disruption of the pyroptotic pore-forming protein gasdermin D inhibits inflammatory cell death and sepsis. Sci. Immunol., 3 https://doi.org/10.1126/ sciimmunol.aat2738. · DOI
  73. Nobel, C.S., Kimland, M., Nicholson, D.W., Orrenius, S., Slater, A.F., (1997). Disulfiram is a potent inhibitor of proteases of the caspase family. Chem. Res. Toxicol., 10, 1319-1324. https://doi.org/10.1021/tx970131m. · DOI
  74. Andrews, N.W., Almeida, P.E., Corrotte, M., (2014). Damage control: cellular mechanisms of plasma membrane repair. Trends Cell Biol., 24, 734-742. https://doi.org/10.1016/j.tcb.2014.07.008. · DOI
  75. Bi, G.Q., Alderton, J.M., Steinhardt, R.A., (1995). Calcium-regulated exocytosis is required for cell membrane resealing. J. Cell Biol., 131, 1747-1758. https://doi.org/10.1083/jcb.131.6.1747. · DOI
  76. Miyake, K., McNeil, P.L., (1995). Vesicle accumulation and exocytosis at sites of plasma membrane disruption. J. Cell Biol., 131, 1737-1745. https://doi.org/10.1083/ jcb.131.6.1737. · DOI
  77. Roy, D., Liston, D.R., Idone, V.J., Di, A., Nelson, D.J., Pujol, C., Bliska, J.B., Chakrabarti, S., et al., (2004). A process for controlling intracellular bacterial infections induced by membrane injury. Science, 304, 1515-1518. https://doi.org/10.1126/science.1098371. · DOI
  78. Forestier, C.-L., Machu, C., Loussert, C., Pescher, P., Spa ¨th, G.F., (2011). Imaging host cell-Leishmania interaction dynamics implicates parasite motility, lysosome recruitment, and host cell wounding in the infection process. Cell Host Microbe, 9, 319-330. https:// doi.org/10.1016/j.chom.2011.03.011. · DOI
  79. Walev, I., Bhakdi, S.C., Hofmann, F., Djonder, N., Valeva, A., Aktories, K., Bhakdi, S., (2001). Delivery of proteins into living cells by reversible membrane permeabilization with streptolysin-O. Proc. Natl. Acad. Sci. USA, 98, 3185- 3190. https://doi.org/10.1073/pnas.051429498. · DOI
  80. Tam, C., Idone, V., Devlin, C., Fernandes, M.C., Flannery, A., He, X., Schuchman, E., Tabas, I., et al., (2010). Exocytosis of acid sphingomyelinase by wounded cells promotes endocytosis and plasma membrane repair. J. Cell Biol., 189, 1027-1038. https://doi.org/10.1083/ jcb.201003053. · DOI
  81. Babiychuk, E.B., Monastyrskaya, K., Draeger, A., (2008). Fluorescent annexin A1 reveals dynamics of ceramide platforms in living cells. Traffic., 9, 1757-1775. https://doi. org/10.1111/j.1600-0854.2008.00800.x. · DOI
  82. Grassme ´, H., Jendrossek, V., Bock, J., Riehle, A., Gulbins, E., (2002). Ceramide-rich membrane rafts mediate CD40 clustering. J. Immunol., 168, 298-307. https://doi.org/10.4049/jimmunol.168.1.298. · DOI
  83. Schissel, S.L., Jiang, X., Tweedie-Hardman, J., Jeong, T., Camejo, E.H., Najib, J., Rapp, J.H., Williams, K.J., et al., (1998). Secretory sphingomyelinase, a product of the acid sphingomyelinase gene, can hydrolyze atherogenic lipoproteins at neutral pH. Implications for atherosclerotic lesion development. J. Biol. Chem., 273, 2738-2746. https://doi.org/10.1074/jbc.273.5.2738. · DOI
  84. van Blitterswijk, W.J., van der Luit, A.H., Veldman, R.J., Verheij, M., Borst, J., (2003). Ceramide: second messenger or modulator of membrane structure and dynamics? Biochem. J., 369, 199-211. https://doi.org/ 10.1042/BJ20021528. · DOI
  85. Gulbins, E., (2003). Regulation of death receptor signaling and apoptosis by ceramide. Pharmacol. Res., 47, 393- 399. https://doi.org/10.1016/s1043-6618(03)00052-5. 100. · DOI
  86. Corrotte, M., Fernandes, M.C., Tam, C., Andrews, N.W., (2012). Toxin pores endocytosed during plasma membrane repair traffic into the lumen of MVBs for degradation. Traffic, 13, 483-494. https://doi.org/10.1111/ j.1600-0854.2011.01323.x. 101. Keefe, D., Shi, L., Feske, S., Massol, R., Navarro, F., Kirchhausen, T., Lieberman, J., (2005). Perforin triggers a plasma membrane-repair response that facilitates CTL induction of apoptosis. Immunity, 23, 249-262. https://doi. org/10.1016/j.immuni.2005.08.001. 102. · DOI
  87. Katzmann, D.J., Odorizzi, G., Emr, S.D., (2002). Receptor downregulation and multivesicular-body sorting. Nature Rev. Mol. Cell Biol., 3, 893-905. https://doi.org/10.1038/ nrm973. 103. Morita, E., Sandrin, V., Chung, H.-Y., Morham, S.G., Gygi, S.P., Rodesch, C.K., Sundquist, W.I., (2007). Human ESCRT and ALIX proteins interact with proteins of the midbody and function in cytokinesis. EMBO J., 26, 4215-4227. https://doi.org/10.1038/sj.emboj.7601850. 104. · DOI · Paper page
  88. Carlton, J.G., Martin-Serrano, J., (2007). Parallels between cytokinesis and retroviral budding: a role for the ESCRT machinery. Science, 316, 1908-1912. https:// doi.org/10.1126/science.1143422. 105. Raab, M., Gentili, M., de Belly, H., Thiam, H.R., Vargas, P., Jimenez, A.J., Lautenschlaeger, F., Voituriez, R., et al., (2016). ESCRT III repairs nuclear envelope ruptures during cell migration to limit DNA damage and cell death. Science, 352, 359-362. https://doi.org/ 10.1126/science.aad7611. 106. Morita, E., Sandrin, V., McCullough, J., Katsuyama, A., Baci Hamilton, I., Sundquist, W.I., (2011). ESCRT-III protein requirements for HIV-1 budding. Cell Host Microbe, 9, 235- 242. https://doi.org/10.1016/j.chom.2011.02.004. 107. · DOI · Paper page
  89. Jimenez, A.J., Maiuri, P., Lafaurie-Janvore, J., Divoux, S., Piel, M., Perez, F., (2014). ESCRT machinery is required for plasma membrane repair. Science, 343, 1247136. https://doi.org/10.1126/science.1247136. 108. Scheffer, L.L., Sreetama, S.C., Sharma, N., Medikayala, S., Brown, K.J., Defour, A., Jaiswal, J.K., (2014). Mechanism of Ca(2)(+)-triggered ESCRT assembly and regulation of cell membrane repair. Nature Commun., 5, 5646. https://doi.org/10.1038/ncomms6646. 109. Gong, Y.N., Guy, C., Olauson, H., Becker, J.U., Yang, M., Fitzgerald, P., Linkermann, A., Green, D.R., (2017). ESCRT-III Acts Downstream of MLKL to Regulate Necroptotic Cell Death and Its Consequences. Cell, 169, 286-300 e16. https://doi.org/10.1016/j.cell.2017.03.020. 110. · DOI · Paper page
  90. Surprenant, A., Rassendren, F., Kawashima, E., North, R. A., Buell, G., (1996). The cytolytic P2Z receptor for extracellular ATP identified as a P2X receptor (P2X7). Science, 272, 735-738. https://doi.org/ 10.1126/science.272.5262.735. 111. North, R.A., (2002). Molecular physiology of P2X receptors. Physiol. Rev., 82, 1013-1067. https://doi.org/ 10.1152/physrev.00015.2002. 112. · DOI · Paper page
  91. Solle, M., Labasi, J., Perregaux, D.G., Stam, E., Petrushova, N., Koller, B.H., Griffiths, R.J., Gabel, C.A., (2001). Altered cytokine production in mice lacking P2X(7) receptors. J. Biol. Chem., 276, 125-132. https://doi.org/ 10.1074/jbc.M006781200. 113. · DOI
  92. Mariathasan, S., Weiss, D.S., Newton, K., McBride, J., O'Rourke, K., Roose-Girma, M., Lee, W.P., Weinrauch, Y., et al., (2006). Cryopyrin activates the inflammasome in response to toxins and ATP. Nature, 440, 228-232. https://doi.org/nature04515 [pii] 10.1038/nature04515. 115. · DOI
  93. Davis, M.A., Fairgrieve, M.R., Den Hartigh, A., Yakovenko, O., Duvvuri, B., Lood, C., Thomas, W.E., Fink, S.L., et al., (2019). Calpain drives pyroptotic vimentin cleavage, intermediate filament loss, and cell rupture that mediates immunostimulation. Proc. Natl. Acad. Sci. USA, 116, 5061-5070. https://doi.org/10.1073/pnas.1818598116. 116. · DOI · Paper page
  94. Orozco, S.L., Daniels, B.P., Yatim, N., Messmer, M.N., Quarato, G., Chen-Harris, H., Cullen, S.P., Snyder, A.G., et al., (2019). RIPK3 Activation Leads to Cytokine Synthesis that Continues after Loss of Cell Membrane Integrity. Cell Rep., 28, 2275-2287.e5. https://doi.org/ 10.1016/j.celrep.2019.07.077. 121. Bootman, M.D., (2012). Calcium signaling. Cold Spring Harb. Perspect. Biol., 4, https://doi.org/10.1101/ cshperspect.a011171 a011171. · DOI

Cited by

Sorted by citations

Authors
Rühl, S., & Broz, P.
Affiliations
St. Jude Children's Research Hospital (US)
ORCID
Rühl, Sebastian
Venue
Journal of Molecular Biology
Publisher
Elsevier BV
Published
2022-02
Volume
434
Issue
4
Pages
167246
ISSN
0022-2836 (ISSN-L)
DOI
10.1016/j.jmb.2021.167246
OpenAlex
W3199367313
Cited by
74
References
7
Citations by year
2026: 10 · 2025: 16 · 2024: 13 · 2023: 20 · 2022: 14 · 2021: 1
FWCI
1.26
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Molecular Biology (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • IRIS (submittedVersion, cc-by-nc-nd)
  • SERVAL (Université de Lausanne) (submittedVersion, cc-by-nc-nd)
Funders
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (310030B_198005)
  • SNF
  • ERC
  • European Research Council (ERC2017-CoG-770988-InflamCellDeath)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords
gasdermin D, pyroptosis, membrane permeabilization, beta-barrel pore, cytokine production, alarmins, ion flux, plasma membrane repair, caspase cleavage, membrane lysis
MeSH terms
Pyroptosis, Gasdermins, Cell Membrane Permeability, Humans, Caspases, Phosphate-Binding Proteins, Pore Forming Cytotoxic Proteins, Inflammasomes

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