Abstract
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.
Key points
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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.
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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.
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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.
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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.
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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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Acknowledgements
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.).
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All authors researched data for and wrote the article. G.P. and N.R. drafted the figures, G.P., A.A. and T.T.P. made substantial contributions to discussion of content, and T.T.P. reviewed/edited the manuscript before submission.
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Glossary
- Apoptosis
-
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.
- Macroautophagy
-
Catabolic process characterized by the formation of intracellular vesicles (‘autophagosomes’) and aiming at the degradation of cellular components through the lysosomal system.
- Mitophagy
-
Selective form of autophagy targeting damaged mitochondria.
- Necroptosis
-
Form of regulated cell death mediated by mixed lineage kinase domain-like pseudokinase pores, whose activation depends on RIPK3 (and RIPK1).
- NETosis
-
Form of regulated cell death restricted to neutrophils that results in the extrusion of neutrophil extracellular traps (NETs).
- Pexophagy
-
Removal of damaged peroxisomes via autophagy.
- Pyroptosis
-
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.
- Receptosome
-
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.
- Yersiniosis
-
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
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DOI: https://doi.org/10.1038/s41575-023-00743-w
