Since the identification and characterization of gasdermin (GSDM) D as the main effector of inflammatory regulated cell death (or pyroptosis), literature on the GSDM family of pore-forming proteins is rapidly expanding, revealing novel mechanisms regulating their expression and functions that go beyond pyroptosis. Indeed, a growing body of evidence corroborates the importance of GSDMs within the gastrointestinal system, underscoring their critical contributions to the pathophysiology of gastrointestinal cancers, enteric infections and gut mucosal inflammation, such as inflammatory bowel disease. However, with this increase in knowledge, several important and controversial issues have arisen regarding basic GSDM biology and its role(s) during health and disease states. These include critical questions centred around GSDM-dependent lytic versus non-lytic functions, the biological activities of cleaved versus full-length proteins, the differential roles of GSDM-expressing mucosal immune versus epithelial cells, and whether GSDMs promote pathogenic or protective effects during specific disease settings. This Review provides a comprehensive summary and interpretation of the current literature on GSDM biology, specifically focusing on the gastrointestinal tract, highlighting the main controversial issues and their clinical implications, and addressing future areas of research to unravel the specific role(s) of this intriguing, yet enigmatic, family of proteins.
The gasdermin (GSDM) family of lipid-binding proteins is involved in several biological processes, with its five members (GSDMA to GSDME) serving as major factors during gastrointestinal health and disease.
GSDMs are primarily known as mediators of pyroptosis; however, evidence supports other roles, including the non-lytic release of inflammatory cytokines, regulation of vital cell functions and targeted bactericidal effects.
The contribution of each GSDM during gastrointestinal health and disease is unequivocal, albeit ambiguous, with reports of both promotion of and protection from gastrointestinal cancers, infections and immune-mediated disorders.
Preliminary evidence suggests potential applications for GSDMs in clinical gastrointestinal practice, with future investigation warranted to leverage their use as predictive or prognostic biomarkers and/or specific therapeutic targets.
Knowledge gaps and controversies exist in GSDM biology regarding their pyroptotic and non-pyroptotic functions and associated signalling pathways, the biological activities of full-length forms, and their roles in immune and non-immune cells.
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Saeki, N., Kuwahara, Y., Sasaki, H., Satoh, H. & Shiroishi, T. Gasdermin (Gsdm) localizing to mouse chromosome 11 is predominantly expressed in upper gastrointestinal tract but significantly suppressed in human gastric cancer cells. Mamm. Genome 11, 718–724 (2000).
Liu, X., Xia, S., Zhang, Z., Wu, H. & Lieberman, J. Channelling inflammation: gasdermins in physiology and disease. Nat. Rev. Drug Discov. 20, 384–405 (2021).
Delmaghani, S. et al. Mutations in the gene encoding pejvakin, a newly identified protein of the afferent auditory pathway, cause DFNB59 auditory neuropathy. Nat. Genet. 38, 770–778 (2006).
Yu, J. et al. Polymorphisms in GSDMA and GSDMB are associated with asthma susceptibility, atopy and BHR. Pediatr. Pulmonol. 46, 701–708 (2011).
Das, S. et al. GSDMB induces an asthma phenotype characterized by increased airway responsiveness and remodeling without lung inflammation. Proc. Natl Acad. Sci. USA 113, 13132–13137 (2016).
Runkel, F. et al. The dominant alopecia phenotypes Bareskin, Rex-denuded, and Reduced Coat 2 are caused by mutations in gasdermin 3. Genomics 84, 824–835 (2004).
Lunny, D. P. et al. Mutations in gasdermin 3 cause aberrant differentiation of the hair follicle and sebaceous gland. J. Invest. Dermatol. 124, 615–621 (2005).
Saeki, N. et al. GASDERMIN, suppressed frequently in gastric cancer, is a target of LMO1 in TGF-β-dependent apoptotic signalling. Oncogene 26, 6488–6498 (2007).
Saeki, N. et al. Distinctive expression and function of four GSDM family genes (GSDMA-D) in normal and malignant upper gastrointestinal epithelium. Genes Chromosomes Cancer 48, 261–271 (2009).
Shi, J. et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526, 660–665 (2015).
Kayagaki, N. et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526, 666–671 (2015).
He, W. T. et al. Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion. Cell Res. 25, 1285–1298 (2015).
Cookson, B. T. & Brennan, M. A. Pro-inflammatory programmed cell death. Trends Microbiol. 9, 113–114 (2001).
Galluzzi, L. et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 25, 486–541 (2018).
Tamura, M. et al. 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 (2007).
Ding, J. et al. Pore-forming activity and structural autoinhibition of the gasdermin family. Nature 535, 111–116 (2016).
Angosto-Bazarra, D. et al. Evolutionary analyses of the gasdermin family suggest conserved roles in infection response despite loss of pore-forming functionality. BMC Biol. 20, 9 (2022).
Rogers, C. et al. Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death. Nat. Commun. 8, 14128 (2017).
Chauhan, D. et al. GSDMD drives canonical inflammasome-induced neutrophil pyroptosis and is dispensable for NETosis. EMBO Rep. https://doi.org/10.15252/EMBR.202154277 (2022).
Kambara, H. et al. Gasdermin D exerts anti-inflammatory effects by promoting neutrophil death. Cell Rep. 22, 2924–2936 (2018).
Sollberger, G. et al. Gasdermin D plays a vital role in the generation of neutrophil extracellular traps. Sci. Immunol. 3, eaar6689 (2018).
Chen, K. W. et al. Noncanonical inflammasome signaling elicits gasdermin D-dependent neutrophil extracellular traps. Sci. Immunol. 3, eaar6676 (2018).
Burgener, S. S. et al. Cathepsin G inhibition by Serpinb1 and Serpinb6 prevents programmed necrosis in neutrophils and monocytes and reduces GSDMD-driven inflammation. Cell Rep. 27, 3646–3656.e5 (2019).
Lin, P. H., Lin, H. Y., Kuo, C. C. & Yang, L. T. N-terminal functional domain of Gasdermin A3 regulates mitochondrial homeostasis via mitochondrial targeting. J. Biomed. Sci. 22, 44 (2015).
Platnich, J. M. et al. Shiga toxin/lipopolysaccharide activates caspase-4 and Gasdermin D to trigger mitochondrial reactive oxygen species upstream of the NLRP3 inflammasome. Cell Rep. 25, 1525–1536.e7 (2018).
Weindel, C. G. et al. Mitochondrial ROS promotes susceptibility to infection via gasdermin D-mediated necroptosis. Cell 185, 3214–3231.e23 (2022).
Rogers, C. et al. Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation. Nat. Commun. 10, 1689 (2019).
Evavold, C. L. et al. The pore-forming protein Gasdermin D regulates interleukin-1 secretion from living macrophages. Immunity 48, 35–44.e6 (2018).
Zanoni, I. et al. An endogenous caspase-11 ligand elicits interleukin-1 release from living dendritic cells. Science 352, 1232–1236 (2016).
Gao, H. et al. Dysregulated microbiota-driven gasdermin D activation promotes colitis development by mediating IL-18 release. Front. Immunol. 12, 750841 (2021).
Huang, J. et al. Famotidine promotes inflammation by triggering cell pyroptosis in gastric cancer cells. BMC Pharmacol. Toxicol. 22, 62 (2021).
Zhao, M. et al. Epithelial STAT6 O-GlcNAcylation drives a concerted anti-helminth alarmin response dependent on tuft cell hyperplasia and Gasdermin C. Immunity https://doi.org/10.1016/J.IMMUNI.2022.03.009 (2022).
Chen, W. et al. Allergen protease-activated stress granule assembly and gasdermin D fragmentation control interleukin-33 secretion. Nat. Immunol. 23, 1021–1030 (2022).
Yamagishi, R. et al. Gasdermin D-mediated release of IL-33 from senescent hepatic stellate cells promotes obesity-associated hepatocellular carcinoma. Sci. Immunol. 7, eabl7209 (2022).
De Torre-Minguela, C., Barberà-Cremades, M., Gómez, A. I., Martín-Sánchez, F. & Pelegrín, P. Macrophage activation and polarization modify P2X7 receptor secretome influencing the inflammatory process. Sci. Rep. 6, 22586 (2016).
Tan, G., Huang, C., Chen, J. & Zhi, F. HMGB1 released from GSDME-mediated pyroptotic epithelial cells participates in the tumorigenesis of colitis-associated colorectal cancer through the ERK1/2 pathway. J. Hematol. Oncol. 13, 149 (2020).
Karmakar, M. et al. N-GSDMD trafficking to neutrophil organelles facilitates IL-1β release independently of plasma membrane pores and pyroptosis. Nat. Commun. 11, 2212 (2020).
Rana, N. et al. GSDMB is increased in IBD and regulates epithelial restitution/repair independent of pyroptosis. Cell https://doi.org/10.1016/j.cell.2021.12.024 (2022).
Bulek, K. et al. Epithelial-derived gasdermin D mediates nonlytic IL-1β release during experimental colitis. J. Clin. Invest. 140, 4218–4234 (2020).
De Schutter, E. et al. GSDME and its role in cancer: from behind the scenes to the front of the stage. Int. J. Cancer 148, 2872–2883 (2021).
Moussette, S. et al. Role of DNA methylation in expression control of the IKZF3-GSDMA region in human epithelial cells. PLoS ONE 12, e0172707 (2017).
Muhammad, J. S. et al. Gasdermin D hypermethylation inhibits pyroptosis and LPS-induced IL-1β release from NK92 cells. Immunotargets Ther. 8, 29–41 (2019).
Stein, M. M. et al. A decade of research on the 17q12-21 asthma locus: piecing together the puzzle. J. Allergy Clin. Immunol. 142, 749–764.e3 (2018).
Taabazuing, C. Y., Okondo, M. C. & Bachovchin, D. A. Pyroptosis and apoptosis pathways engage in bidirectional crosstalk in monocytes and macrophages. Cell Chem. Biol. 24, 507–514.e4 (2017).
Chao, K. L., Kulakova, L. & Herzberg, O. 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 (2017).
Devant, P. et al. Gasdermin D pore-forming activity is redox-sensitive. Cell Rep. 42, 112008 (2023).
Humphries, F. et al. Succination inactivates gasdermin D and blocks pyroptosis. Science 369, 1633–1637 (2020).
Hu, L. et al. Chemotherapy-induced pyroptosis is mediated by BAK/BAX-caspase-3-GSDME pathway and inhibited by 2-bromopalmitate. Cell Death Dis. 11, 281 (2020).
Bambouskova, M. et al. Itaconate confers tolerance to late NLRP3 inflammasome activation. Cell Rep. 34, 108756 (2021).
Rühl, S. et al. ESCRT-dependent membrane repair negatively regulates pyroptosis downstream of GSDMD activation. Science 362, 956–960 (2018).
Santa Cruz Garcia, A. B., Schnur, K. P., Malik, A. B. & Mo, G. C. H. Gasdermin D pores are dynamically regulated by local phosphoinositide circuitry. Nat. Commun. 13, 52 (2022).
Hou, J., Hsu, J.-M. & Hung, M.-C. Molecular mechanisms and functions of pyroptosis in inflammation and antitumor immunity. Mol. Cell https://doi.org/10.1016/j.molcel.2021.09.003 (2021).
Privitera, G., Rana, N., Scaldaferri, F., Armuzzi, A. & Pizarro, T. T. Novel insights into the interactions between the gut microbiome, inflammasomes, and gasdermins during colorectal cancer. Front. Cell. Infect. Microbiol. 11, 806680 (2022).
Wu, C. et al. Inflammasome activation triggers blood clotting and host death through pyroptosis. Immunity 50, 1401–1411.e4 (2019).
Yang, X. et al. Bacterial endotoxin activates the coagulation cascade through Gasdermin D-dependent phosphatidylserine exposure. Immunity 51, 983–996.e6 (2019).
McDonald, B. et al. Platelets and neutrophil extracellular traps collaborate to promote intravascular coagulation during sepsis in mice. Blood 129, 1357–1367 (2017).
Solem, C. A., Loftus, E. V., Tremaine, W. J. & Sandborn, W. J. Venous thromboembolism in inflammatory bowel disease. Am. J. Gastroenterol. 99, 97–101 (2004).
Zou, J. et al. The versatile gasdermin family: their function and roles in diseases. Front. Immunol. 12, 751533 (2021).
Tan, G., Huang, C., Chen, J., Chen, B. & Zhi, F. Gasdermin-E-mediated pyroptosis participates in the pathogenesis of Crohn’s disease by promoting intestinal inflammation. Cell Rep. 35, 109265 (2021).
Katoh, M. & Katoh, M. Identification and characterization of human DFNA5L, mouse Dfna5l, and rat Dfna5l genes in silico. Int. J. Oncol. 25, 765–770 (2004).
Kusumaningrum, N. et al. Gasdermin C is induced by ultraviolet light and contributes to MMP-1 expression via activation of ERK and JNK pathways. J. Dermatol. Sci. 90, 180–189 (2018).
Terao, C. et al. Transethnic meta-analysis identifies GSDMA and PRDM1 as susceptibility genes to systemic sclerosis. Ann. Rheum. Dis. 76, 1150–1158 (2017).
Söderman, J., Berglind, L. & Almer, S. Gene expression-genotype analysis implicates GSDMA, GSDMB, and LRRC3C as contributors to inflammatory bowel disease susceptibility. Biomed. Res. Int. 2015, 834805 (2015).
Shi, P. et al. Loss of conserved Gsdma3 self-regulation causes autophagy and cell death. Biochem. J. 468, 325–336 (2015).
Deng, W. et al. Streptococcal pyrogenic exotoxin B cleaves GSDMA and triggers pyroptosis. Nature 602, 496–502 (2022).
LaRock, D. L. et al. Group A Streptococcus induces GSDMA-dependent pyroptosis in keratinocytes. Nature 605, 527–531 (2022).
Ruan, J. Structural insight of Gasdermin family driving pyroptotic cell death. Adv. Exp. Med. Biol. 1172, 189–205 (2019).
Chen, Q. et al. GSDMB promotes non-canonical pyroptosis by enhancing caspase-4 activity. J. Mol. Cell Biol. 11, 496–508 (2019).
Panganiban, R. A. et al. A functional splice variant associated with decreased asthma risk abolishes the ability of gasdermin B to induce epithelial cell pyroptosis. J. Allergy Clin. Immunol. 142, 1469–1478.e2 (2018).
Zhou, Z. et al. Granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells. Science 368, eaaz7548 (2020).
Zeng, R. et al. Predicting the prognosis of esophageal adenocarcinoma by a pyroptosis-related gene signature. Front. Pharmacol. 12, 3142 (2021).
Komiyama, H. et al. Alu-derived cis-element regulates tumorigenesis-dependent gastric expression of GASDERMIN B (GSDMB). Genes Genet. Syst. 85, 75–83 (2010).
Carl-McGrath, S., Schneider-Stock, R., Ebert, M. & Röcken, C. Differential expression and localisation of gasdermin-like (GSDML), a novel member of the cancer-associated GSDMDC protein family, in neoplastic and non-neoplastic gastric, hepatic, and colon tissues. Pathology 40, 13–24 (2008).
Hansen, J. M. et al. Pathogenic ubiquitination of GSDMB inhibits NK cell bactericidal functions. Cell 184, 3178–3191.e18 (2021).
Miguchi, M. et al. Gasdermin C is upregulated by inactivation of transforming growth factor β receptor type II in the presence of mutated Apc, promoting colorectal cancer proliferation. PLoS ONE 11, e0166422 (2016).
Hou, J. et al. PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumour necrosis. Nat. Cell Biol. 22, 1264–1275 (2020).
Zhang, J.-Y. et al. The metabolite α-KG induces GSDMC-dependent pyroptosis through death receptor 6-activated caspase-8. Cell Res. 31, 980–997 (2021).
Xi, R. et al. Up-regulation of gasdermin C in mouse small intestine is associated with lytic cell death in enterocytes in worm-induced type 2 immunity. Proc. Natl Acad. Sci. USA 118, e2026307118 (2021).
Dinarello, C. A. Overview of the IL-1 family in innate inflammation and acquired immunity. Immunol. Rev. 281, 8–27 (2018).
Zanoni, I., Tan, Y., Di Gioia, M., Springstead, J. R. & Kagan, J. C. By capturing inflammatory lipids released from dying cells, the receptor CD14 induces inflammasome-dependent phagocyte hyperactivation. Immunity 47, 697–709.e3 (2017).
Chen, K. W. et al. The neutrophil NLRC4 inflammasome selectively promotes IL-1β maturation without pyroptosis during acute Salmonella challenge. Cell Rep. 8, 570–582 (2014).
Zhang, J. et al. Epithelial Gasdermin D shapes the host-microbial interface by driving mucus layer formation. Sci. Immunol. 7, eabk2092 (2022).
Ma, Y., Chen, Y., Lin, C. & Hu, G. Biological functions and clinical significance of the newly identified long non-coding RNA RP1-85F18.6 in colorectal cancer. Oncol. Rep. 40, 2648–2658 (2018).
Wu, L. S. et al. LPS enhances the chemosensitivity of oxaliplatin in HT29 cells via GSDMD-mediated pyroptosis. Cancer Manag. Res. 12, 10397–10409 (2020).
Wang, W. J. et al. Downregulation of gasdermin D promotes gastric cancer proliferation by regulating cell cycle-related proteins. J. Dig. Dis. 19, 74–83 (2018).
Wang, L. et al. Metformin induces human esophageal carcinoma cell pyroptosis by targeting the miR-497/PELP1 axis. Cancer Lett. 450, 22–31 (2019).
Mileykovskaya, E. & Dowhan, W. Cardiolipin membrane domains in prokaryotes and eukaryotes. Biochim. Biophys. Acta 1788, 2084 (2009).
Liu, X. et al. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 535, 153–158 (2016).
Papayannopoulos, V. Neutrophil extracellular traps in immunity and disease. Nat. Rev. Immunol. 18, 134–147 (2018).
Jorgensen, I., Zhang, Y., Krantz, B. A. & Miao, E. A. Pyroptosis triggers pore-induced intracellular traps (PITs) that capture bacteria and lead to their clearance by efferocytosis. J. Exp. Med. 213, 2113–2128 (2016).
Orning, P. et al. Pathogen blockade of TAK1 triggers caspase-8-dependent cleavage of gasdermin D and cell death. Sci 362, 1064–1069 (2018).
Sarhan, J. et al. Caspase-8 induces cleavage of gasdermin D to elicit pyroptosis during Yersinia infection. Proc. Natl Acad. Sci. USA 115, E10888–E10897 (2018).
Demarco, B. et al. Caspase-8-dependent gasdermin D cleavage promotes antimicrobial defense but confers susceptibility to TNF-induced lethality. Sci. Adv. 6, 3465–3483 (2020).
Wang, Y. et al. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature 547, 99–103 (2017).
Jiang, M., Qi, L., Li, L. & Li, Y. The caspase-3/GSDME signal pathway as a switch between apoptosis and pyroptosis in cancer. Cell Death Discov. 6, 112 (2020).
Zhang, Z. et al. Gasdermin E suppresses tumour growth by activating anti-tumour immunity. Nature 579, 415–420 (2020).
Aizawa, E. et al. GSDME-dependent incomplete pyroptosis permits selective IL-1α release under caspase-1 inhibition. iScience 23, 101070 (2020).
Zhou, B. & Abbott, D. W. Gasdermin E permits interleukin-1 beta release in distinct sublytic and pyroptotic phases. Cell Rep. 35, 108998 (2021).
Chen, K. W. et al. RIPK1 activates distinct gasdermins in macrophages and neutrophils upon pathogen blockade of innate immune signaling. Proc. Natl Acad. Sci. USA 118, e2101189118 (2021).
Tan, G. et al. An IRF1-dependent pathway of TNFα-induced shedding in intestinal epithelial cells. J. Crohns Colitis 16, 133–142 (2022).
Yokomizo, K. et al. Methylation of the DFNA5 gene is frequently detected in colorectal cancer. Anticancer. Res. 32, 1319–1322 (2012).
Wu, M. et al. A PLK1 kinase inhibitor enhances the chemosensitivity of cisplatin by inducing pyroptosis in oesophageal squamous cell carcinoma. EBioMedicine 41, 244–255 (2019).
Zhang, Z. et al. Prognostic and immunological role of Gasdermin E in pan-cancer analysis. Front. Oncol. 11, 2879 (2021).
Su, F. et al. Long non-coding RNA nuclear paraspeckle assembly transcript 1 regulates ionizing radiation-induced pyroptosis via microRNA-448/gasdermin E in colorectal cancer cells. Int. J. Oncol. 59, 79 (2021).
Yu, J. et al. Cleavage of GSDME by caspase-3 determines lobaplatin-induced pyroptosis in colon cancer cells. Cell Death Dis. 10, 193 (2019).
Wang, Y. et al. GSDME mediates caspase-3-dependent pyroptosis in gastric cancer. Biochem. Biophys. Res. Commun. 495, 1418–1425 (2018).
Orzalli, M. H. et al. Virus-mediated inactivation of anti-apoptotic Bcl-2 family members promotes Gasdermin-E-dependent pyroptosis in barrier epithelial cells. Immunity 54, 1447–1462.e5 (2021).
Mujtaba, G., Bukhari, I., Fatima, A. & Naz, S. A p.C343S missense mutation in PJVK causes progressive hearing loss. Gene 504, 98–101 (2012).
Delmaghani, S. et al. Hypervulnerability to sound exposure through impaired adaptive proliferation of peroxisomes. Cell 163, 894–906 (2015).
Defourny, J. et al. Pejvakin-mediated pexophagy protects auditory hair cells against noise-induced damage. Proc. Natl Acad. Sci. USA 116, 8010–8017 (2019).
Spechler, S. J. Barrett esophagus and risk of esophageal cancer: a clinical review. JAMA 310, 627–636 (2013).
Correa, P. & Houghton, J. M. Carcinogenesis of Helicobacter pylori. Gastroenterology 133, 659–672 (2007).
Axelrad, J. E., Lichtiger, S. & Yajnik, V. Inflammatory bowel disease and cancer: the role of inflammation, immunosuppression, and cancer treatment. World J. Gastroenterol. 22, 4794 (2016).
Hergueta-Redondo, M. et al. Gasdermin-B promotes invasion and metastasis in breast cancer cells. PLoS ONE 9, e90099 (2014).
Mu, M. et al. A pan-cancer analysis of molecular characteristics and oncogenic role of gasdermins. Cancer Cell Int. 22, 80 (2022).
Croes, L. et al. Determination of the potential tumor-suppressive effects of Gsdme in a chemically induced and in a genetically modified intestinal cancer mouse model. Cancers 11, 1214 (2019).
Santiago, L. et al. Extracellular granzyme A promotes colorectal cancer development by enhancing gut inflammation. Cell Rep. 32, 107847 (2020).
Zheng, Z. Y. et al. STAT3β disrupted mitochondrial electron transport chain enhances chemosensitivity by inducing pyroptosis in esophageal squamous cell carcinoma. Cancer Lett. 522, 171–183 (2021).
Li, L. et al. Photodynamic therapy induces human esophageal carcinoma cell pyroptosis by targeting the PKM2/caspase-8/caspase-3/GSDME axis. Cancer Lett. 520, 143–159 (2021).
Tan, G. et al. Radiosensitivity of colorectal cancer and radiation-induced gut damages are regulated by gasdermin E. Cancer Lett. 529, 1–10 (2022).
Thurston, T. L. M. et al. Growth inhibition of cytosolic Salmonella by caspase-1 and caspase-11 precedes host cell death. Nat. Commun. 7, 13292 (2016).
Zuo, L. et al. Salmonella spvC gene inhibits pyroptosis and intestinal inflammation to aggravate systemic infection in mice. Front. Microbiol. 11, 3135 (2020).
Havira, M. S. et al. Shiga toxin suppresses noncanonical inflammasome responses to cytosolic LPS. Sci. Immunol. 5, eabc0217 (2020).
Tsutsuki, H. et al. Subtilase cytotoxin from Shiga-toxigenic Escherichia coli impairs the inflammasome and exacerbates enteropathogenic bacterial infection. iScience 25, 104050 (2022).
Luchetti, G. et al. Shigella ubiquitin ligase IpaH7.8 targets gasdermin D for degradation to prevent pyroptosis and enable infection. Cell Host Microbe 29, 1521–1530.e10 (2021).
Rauch, I. et al. NAIP-NLRC4 inflammasomes coordinate intestinal epithelial cell expulsion with eicosanoid and IL-18 release via activation of caspase-1 and -8. Immunity 46, 649–659 (2017).
Ventayol, P. S. et al. Bacterial detection by NAIP/NLRC4 elicits prompt contractions of intestinal epithelial cell layers. Proc. Natl Acad. Sci. USA 118, e2013963118 (2021).
Sellin, M. E. et al. Epithelium-intrinsic NAIP/NLRC4 inflammasome drives infected enterocyte expulsion to restrict Salmonella replication in the intestinal mucosa. Cell Host Microbe 16, 237–248 (2014).
Knodler, L. A. et al. Noncanonical inflammasome activation of caspase-4/caspase-11 mediates epithelial defenses against enteric bacterial pathogens. Cell Host Microbe 16, 249–256 (2014).
Fattinger, S. A., Sellin, M. E. & Hardt, W. D. Epithelial inflammasomes in the defense against Salmonella gut infection. Curr. Opin. Microbiol. 59, 86–94 (2021).
Fattinger, S. A. et al. Epithelium-autonomous NAIP/NLRC4 prevents TNF-driven inflammatory destruction of the gut epithelial barrier in Salmonella-infected mice. Mucosal Immunol. 14, 615–629 (2021).
Zhong, Q. et al. Clustering of Tir during enteropathogenic E. coli infection triggers calcium influx–dependent pyroptosis in intestinal epithelial cells. PLoS Biol. 18, e3000986 (2020).
Man, S. M. Inflammasomes in the gastrointestinal tract: infection, cancer and gut microbiota homeostasis. Nat. Rev. Gastroenterol. Hepatol. 15, 721–737 (2018).
Shi, Y. et al. Host Gasdermin D restrains systemic endotoxemia by capturing Proteobacteria in the colon of high-fat diet-feeding mice. Gut Microbes 13, 1946369 (2021).
Quach, J., Moreau, F., Sandall, C. & Chadee, K. Entamoeba histolytica-induced IL-1β secretion is dependent on caspase-4 and gasdermin D. Mucosal Immunol. 12, 323–339 (2019).
Wang, S., Moreau, F. & Chadee, K. The colonic pathogen Entamoeba histolytica activates caspase-4/1 that cleaves the pore-forming protein gasdermin D to regulate IL-1β secretion. PLoS Pathog. 18, e1010415 (2022).
Li, J. et al. Insight to pyroptosis in viral infectious diseases. Health 13, 574–590 (2021).
Zhu, S. et al. Nlrp9b inflammasome restricts rotavirus infection in intestinal epithelial cells. Nature 546, 667–670 (2017).
Dubois, H. et al. Nlrp3 inflammasome activation and Gasdermin D-driven pyroptosis are immunopathogenic upon gastrointestinal norovirus infection. PLoS Pathog. 15, e1007709 (2019).
Dong, S. et al. Gasdermin E is required for induction of pyroptosis and severe disease during enterovirus 71 infection. J. Biol. Chem. 298, 101850 (2022).
Lei, X. et al. Enterovirus 71 inhibits pyroptosis through cleavage of Gasdermin D. J. Virol. 91, e01069-17 (2017).
Wang, W. et al. EV71 3D protein binds with NLRP3 and enhances the assembly of inflammasome complex. PLoS Pathog. 13, e1006123 (2017).
Wang, Y. et al. Pyroptosis induced by enterovirus 71 and coxsackievirus B3 infection affects viral replication and host response Sci. Rep. 8, 2887 (2018).
Briardi, B., Malireddi, R. K. S. & Kannegantii, T. D. Role of inflammasomes/pyroptosis and PANoptosis during fungal infection. PLoS Pathog. 17, e1009358 (2021).
De Schutter, E. et al. Punching holes in cellular membranes: biology and evolution of gasdermins. Trends Cell Biol. 31, 500–513 (2021).
Jiang, S., Zhou, Z., Sun, Y., Zhang, T. & Sun, L. Coral gasdermin triggers pyroptosis. Sci. Immunol. 5, eabd2591 (2020).
IBD Exomes Portal. Gene: GSDMB. IBD Exomes Browser https://dmz-ibd.broadinstitute.org/gene/ENSG00000073605 (2023).
Jostins, L. et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012).
Gong, W., Liu, P. & Ren, J. GSDMB-mediated pyroptosis exacerbates intestinal inflammation by destroying intestinal epithelium in Crohn’s disease [abstract P010]. Presented at the 16th Congress of ECCO. https://www.ecco-ibd.eu/publications/congress-abstracts/item/p010-gsdmb-mediated-pyroptosis-exacerbates-intestinal-inflammation-by-destroying-intestinal-epithelium-in-crohn-s-disease.html (2021).
Ma, C. et al. Gasdermin D in macrophages restrains colitis by controlling cGAS-mediated inflammation. Sci. Adv. 6, eaaz6717 (2020).
Schwarzer, R., Jiao, H., Wachsmuth, L., Tresch, A. & Pasparakis, M. FADD and caspase-8 regulate gut homeostasis and inflammation by controlling MLKL- and GSDMD-mediated death of intestinal epithelial cells. Immunity 52, 978–993.e6 (2020).
Chen, X. et al. NEK7 interacts with NLRP3 to modulate the pyroptosis in inflammatory bowel disease via NF-κB signaling. Cell Death Dis. 10, 906 (2019).
Gao, W. et al. TRIM21 regulates pyroptotic cell death by promoting Gasdermin D oligomerization. Cell Death Differ. 29, 439–450 (2022).
Luo, B., Lin, J., Cai, W. & Wang, M. Identification of the pyroptosis-related gene signature and risk score model for colon adenocarcinoma. Front. Genet. 12, 2450 (2021).
Qiu, S., Hu, Y. & Dong, S. Pan-cancer analysis reveals the expression, genetic alteration and prognosis of pyroptosis key gene GSDMD. Int. Immunopharmacol. 101, 108270 (2021).
Wang, J. et al. Gasdermin D in different subcellular locations predicts diverse progression, immune microenvironment and prognosis in colorectal cancer. J. Inflamm. Res. 14, 6223–6235 (2021).
Ibrahim, J. et al. Methylation analysis of Gasdermin E shows great promise as a biomarker for colorectal cancer. Cancer Med. 8, 2133–2145 (2019).
Fu, L. et al. Intracellular MUC20 variant 2 maintains mitochondrial calcium homeostasis and enhances drug resistance in gastric cancer. Gastric Cancer 25, 542–557 (2022).
Hergueta-Redondo, M. et al. Gasdermin B expression predicts poor clinical outcome in HER2-positive breast cancer. Oncotarget 7, 56295–56308 (2016).
Gunturu, K. S., Woo, Y., Beaubier, N., Remotti, H. E. & Saif, M. W. Gastric cancer and trastuzumab: first biologic therapy in gastric cancer. Ther. Adv. Med. Oncol. 5, 143 (2013).
Homsy, E. et al. Circulating Gasdermin-D in critically ill patients. Crit. Care Explor. 1, e0039 (2019).
Deng, B. B., Jiao, B. P., Liu, Y. J., Li, Y. R. & Wang, G. J. BIX-01294 enhanced chemotherapy effect in gastric cancer by inducing GSDME-mediated pyroptosis. Cell Biol. Int. 44, 1890–1899 (2020).
Shen, X., Wang, H., Weng, C., Jiang, H. & Chen, J. Caspase 3/GSDME-dependent pyroptosis contributes to chemotherapy drug-induced nephrotoxicity. Cell Death Dis. 12, 186 (2021).
Huang, Z. et al. Inhibition of caspase-3-mediated GSDME-derived pyroptosis aids in noncancerous tissue protection of squamous cell carcinoma patients during cisplatin-based chemotherapy. Am. J. Cancer Res. 10, 4287 (2020).
Jiang, S. et al. Vitamin D/VDR attenuate cisplatin-induced AKI by down-regulating NLRP3/caspase-1/GSDMD pyroptosis pathway. J. Steroid Biochem. Mol. Biol. 206, 105789 (2021).
Liu, Y. et al. Gasdermin E-mediated target cell pyroptosis by CAR T cells triggers cytokine release syndrome. Sci. Immunol. 5, eaax7969 (2020).
Xiao, Y. et al. Microenvironment-responsive prodrug-induced pyroptosis boosts cancer immunotherapy. Adv. Sci. 8, 2101840 (2021).
Liu, Z. et al. Apoptin induces pyroptosis of colorectal cancer cells via the GSDME-dependent pathway. Int. J. Biol. Sci. 18, 717 (2022).
Molina-Crespo, A. et al. Intracellular delivery of an antibody targeting gasdermin-B reduces HER2 breast cancer aggressiveness. Clin. Cancer Res. 25, 4846–4858 (2019).
Gámez-Chiachio, M. et al. Gasdermin B over-expression modulates HER2-targeted therapy resistance by inducing protective autophagy through Rab7 activation. J. Exp. Clin. Cancer Res. 41, 285 (2022).
Wang, Q. et al. A bioorthogonal system reveals antitumour immune function of pyroptosis. Nature 579, 421–426 (2020).
Ryder, C. B., Kondolf, H. C., O’Keefe, M. E., Zhou, B. & Abbott, D. W. Chemical modulation of gasdermin-mediated pyroptosis and therapeutic potential. J. Mol. Biol. 434, 167183 (2022).
Rathkey, J. K. et al. Chemical disruption of the pyroptotic pore-forming protein gasdermin D inhibits inflammatory cell death and sepsis. Sci. Immunol. 3, eaat2738 (2018).
Hu, J. J. et al. FDA-approved disulfiram inhibits pyroptosis by blocking gasdermin D pore formation. Nat. Immunol. 21, 736–745 (2020).
Ou, Ate et al. Disulfiram-loaded lactoferrin nanoparticles for treating inflammatory diseases. Acta Pharmacol. Sin. 42, 1913–1920 (2021).
Feagan, B. G. et al. A comparison of methotrexate with placebo for the maintenance of remission in Crohn’s disease. N. Engl. J. Med. 342, 1627–1632 (2000).
Feagan, B. G. et al. Methotrexate for the treatment of Crohn’s disease. N. Engl. J. Med. 332, 292–297 (1995).
Privitera, G. & Pizarro, T. T. Live or let die: translational insights and clinical perspectives of gasdermin B-dependent intestinal epithelial cell fate. Clin. Transl. Med. 12, e787 (2022).
Al Mamun, A. et al. Role of pyroptosis in liver diseases. Int. Immunopharmacol. 84, 106489 (2020).
Rodríguez-Antonio, I., López-Sánchez, G. N., Uribe, M., Chávez-Tapia, N. C. & Nuño-Lámbarri, N. Role of the inflammasome, gasdermin D, and pyroptosis in non-alcoholic fatty liver disease. J. Gastroenterol. Hepatol. 36, 2720–2727 (2021).
Gaul, S. et al. Hepatocyte pyroptosis and release of inflammasome particles induce stellate cell activation and liver fibrosis. J. Hepatol. 74, 156–167 (2021).
Xu, W. F. et al. Gasdermin E-derived caspase-3 inhibitors effectively protect mice from acute hepatic failure. Acta Pharmacol. Sin. 42, 68–76 (2021).
Lin, T. et al. Downregulating Gasdermin D reduces severe acute pancreatitis associated with pyroptosis. Med. Sci. Monit. 27, e927968 (2021).
Wu, J. et al. Treatment of severe acute pancreatitis and related lung injury by targeting Gasdermin D-mediated pyroptosis. Front. Cell Dev. Biol. 9, 780142 (2021).
Chen, Y. et al. Ultraviolet B induces proteolytic cleavage of the pyroptosis inducer gasdermin E in keratinocytes. J. Dermatol. Sci. 100, 160–163 (2020).
Grossi, S. et al. Inactivation of the cytoprotective major vault protein by caspase-1 and -9 in epithelial cells during apoptosis. J. Invest. Dermatol. 140, 1335–1345.e10 (2020).
Ruan, J., Xia, S., Liu, X., Lieberman, J. & Wu, H. Cryo-EM structure of the gasdermin A3 membrane pore. Nature 557, 62–67 (2018).
Liu, Z. et al. Crystal structures of the full-length murine and human Gasdermin D reveal mechanisms of autoinhibition, lipid binding, and oligomerization. Immunity 51, 43–49.e4 (2019).
Xia, S. et al. Gasdermin D pore structure reveals preferential release of mature interleukin-1. Nature 593, 607–611 (2021).
Chen, X. et al. Pyroptosis is driven by non-selective gasdermin-D pore and its morphology is different from MLKL channel-mediated necroptosis. Cell Res. 26, 1007–1020 (2016).
Zheng, Z. et al. The lysosomal Rag-Ragulator complex licenses RIPK1- and caspase-8-mediated pyroptosis by Yersinia. Science 372, eabg0269 (2021).
Lei, M. et al. Gsdma3 is a new factor needed for TNF-α-mediated apoptosis signal pathway in mouse skin keratinocytes. Histochem. Cell Biol. 138, 385–396 (2012).
Kayagaki, N. et al. IRF2 transcriptionally induces GSDMD expression for pyroptosis. Sci. Signal. 12, eaax4917 (2019).
Benaoudia, S. et al. A genome-wide screen identifies IRF2 as a key regulator of caspase-4 in human cells. EMBO Rep. 20, e48235 (2019).
Saeki, N. & Hiroki, S. in Endothelium and Epithelium: Composition, Functions, and Pathology (eds Carrasco, J. & Mota, M.) 193–211 (Nova Biomedical, 2012).
Pandey, A., Shen, C., Feng, S. & Man, S. M. Cell biology of inflammasome activation. Trends Cell Biol. 31, 924–939 (2021).
Pandey, A., Shen, C. & Man, S. M. Inflammasomes in colitis and colorectal cancer: mechanism of action and therapies. Yale J. Biol. Med. 92, 481–498 (2019).
Liu, Z. et al. Caspase-1 engages full-length Gasdermin D through two distinct interfaces that mediate caspase recruitment and substrate cleavage. Immunity 53, 106–114.e5 (2020).
Dinarello, C. et al. IL-1 family nomenclature. Nat. Immunol. 11, 973 (2010).
Rivers-Auty, J. & Brough, D. Potassium efflux fires the canon: potassium efflux as a common trigger for canonical and noncanonical NLRP3 pathways. Eur. J. Immunol. 45, 2758–2761 (2015).
Yu, P. et al. Pyroptosis: mechanisms and diseases. Signal. Transduct. Target. Ther. 6, 128 (2021).
Bedoui, S., Herold, M. J. & Strasser, A. Emerging connectivity of programmed cell death pathways and its physiological implications. Nat. Rev. Mol. Cell Biol. 21, 678–695 (2020).
Labani-Motlagh, A., Ashja-Mahdavi, M. & Loskog, A. The tumor microenvironment: a milieu hindering and obstructing antitumor immune responses. Front. Immunol. 11, 940 (2020).
Colegio, O. R. et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513, 559–563 (2014).
Gül, N. et al. Macrophages eliminate circulating tumor cells after monoclonal antibody therapy. J. Clin. Invest. 124, 812–823 (2014).
Yu, J. et al. Myeloid-derived suppressor cells suppress antitumor immune responses through IDO expression and correlate with lymph node metastasis in patients with breast cancer. J. Immunol. 190, 3783–3797 (2013).
Kobayashi, N. et al. FOXP3+ regulatory T cells affect the development and progression of hepatocarcinogenesis. Clin. Cancer Res. 13, 902–911 (2007).
Hoepner, S. et al. Synergy between CD8 T cells and Th1 or Th2 polarised CD4 T cells for adoptive immunotherapy of brain tumours. PLoS ONE 8, e63933 (2013).
Weigelin, B. et al. Cytotoxic T cells are able to efficiently eliminate cancer cells by additive cytotoxicity. Nat. Commun. 12, 5217 (2021).
Melaiu, O., Lucarini, V., Cifaldi, L. & Fruci, D. Influence of the tumor microenvironment on NK cell function in solid tumors. Front. Immunol. 10, 3038 (2020).
Jiang, W. et al. Exhausted CD8+ T cells in the tumor immune microenvironment: new pathways to therapy. Front. Immunol. 11, 3739 (2021).
The authors acknowledge continued support for this work from the NIH/NIDDK and NIAID: DK091222 (P01 Project 3), DK042191, DK125293 and AI141350 (P01 Project 4) (to T.T.P.).
All authors declare no competing interests.
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Nature Reviews Gastroenterology & Hepatology thanks Kaiwen Chen, Hai-Bin Ruan, Xing Liu, and the other, anonymous, reviewer for their contribution to the peer review of this work.
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Form of regulated cell death under the control of executioner caspases that results in the formation of intact vesicles (apoptotic bodies).
- Enterovirus 71
Enterovirus with faecal–oral transmission that is the primary causative agent of ‘hand, foot and mouth disease’.
- Inflammatory bowel disease
Chronic inflammatory condition with a relapsing–remitting course that affects (primarily) the gastrointestinal tract; it arises from dysregulated interactions between the host immune system and its gut microbiome, and its main clinical phenotype is represented by Crohn’s disease and ulcerative colitis.
Catabolic process characterized by the formation of intracellular vesicles (‘autophagosomes’) and aiming at the degradation of cellular components through the lysosomal system.
Selective form of autophagy targeting damaged mitochondria.
Form of regulated cell death mediated by mixed lineage kinase domain-like pseudokinase pores, whose activation depends on RIPK3 (and RIPK1).
Form of regulated cell death restricted to neutrophils that results in the extrusion of neutrophil extracellular traps (NETs).
Removal of damaged peroxisomes via autophagy.
Form of regulated cell death that depends on the formation of GSDM pores on the cell plasma membrane; it is often (but not always) a consequence of inflammatory caspase activation, and is usually associated with the release of inflammatory mediators into the extracellular space.
Intracellular vesicle that is formed via concentrative, receptor-mediated endocytosis, possibly with the ligand–receptor complex still bound to the membrane.
- Regulated cell death
Form of cell death dependent on the activation of specific signal transducers and terminal effectors; it is susceptible to chemical and/or pharmacological modulations (including both apoptosis and a form of inflammatory cell death).
- Salmonella enterica subsp. enterica serovar Typhimurium
Facultative intracellular pathogen that causes food-borne infectious colitis in mice; it is used as a model of human typhoid fever (caused by S. Typhi).
- Secondary necrosis
Event following end-stage apoptosis in vitro or in vivo when phagocytic clearance of apoptotic bodies fails resulting in plasma membrane rupture and release of cytoplasmic contents.
Food-borne gastrointestinal infection with pathogens localizing to intestinal lymphoid tissues and mesenteric lymph nodes: it is clinically characterized by abdominal pain and diarrhoea and is usually caused by Yersinia enterocolitica; Y. pseudotuberculosis is commonly used in mouse models of yersiniosis but rarely causes yersiniosis in humans.
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Privitera, G., Rana, N., Armuzzi, A. et al. The gasdermin protein family: emerging roles in gastrointestinal health and disease. Nat Rev Gastroenterol Hepatol 20, 366–387 (2023). https://doi.org/10.1038/s41575-023-00743-w