The gasdermin protein family: emerging roles in gastrointestinal health and disease

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.

Fig. 1 ∣. Important features of gasdermins.

Schematic representation of the most important features of gasdermins (GSDMs). The activation pathways of full-length GSDMs are not fully understood. Two major pathways have been identified for cleaved GSDMs: caspase-dependent (with or without the involvement of the inflammasome) and caspase-independent (requiring different proteases). GSDMs can target either human cells (immune and non-immune) and/or bacterial cells. GSDM functions can be schematically classified as pore-forming (that is, pyroptosis and cytokine release) and non-pore-forming (including cell proliferation and pore-independent cytokine release). GSDM activation can occur acutely (resulting in either pyroptosis or definitive membrane repair) or chronically (with continuous pore formation counterbalanced by repair mechanisms). Within eukaryotic cells, GSDMs can be found in different locations: intracytoplasmic or nuclear, or bound to lipid membranes (that is, plasma or organelle membranes). ELANE, neutrophil elastase; NK, natural killer.

Fig. 2 ∣. Role and contribution of epithelial-derived gasdermins in gastrointestinal cancers.

Cleaved gasdermins (GSDMs) contribute to gastrointestinal carcinogenesis by mediating pyroptotic cell death and/or sublytic release of inflammatory mediators. Chronic intestinal inflammation, secondary to GSDM-dependent release of intracellular mediators, is a pro-carcinogenic stimulus that perpetuates tumorigenesis. GSDM-mediated pyroptosis of cancer cells can exert a direct antitumour effect by killing neoplastic clones, thereby reducing the tumour burden. Finally, the GSDM-dependent release of intracellular mediators from neoplastic cells shapes the tumour microenvironment to promote either antitumour or pro-tumour functions in relation to the specific leukocyte subpopulations that are recruited and activated. Full-length GSDMs can also affect the pathogenesis of cancer. GSDMB, GSDMC and GSDME are involved in the proliferation, migration and adhesion of intestinal epithelial cells, all of which are critical components for the development and growth of malignancies. Lastly, as IL-1β has been reported to play a role in the pathogenesis of gastrointestinal cancer, it is possible that the specific form of IL-1β release (and potentially, of other cytokines belonging to the IL-1 superfamily) mediated by GSDMs might also contribute to carcinogenesis. HMGB1, high-mobility group box protein 1.

Fig. 3 ∣. Role and contribution of gasdermins in gastrointestinal inflammation.

a, Gasdermins (GSDMs) facilitate host–bacteria interactions within the gut. GSDMD-amino-terminal (GSDMD-NT) mediates NETosis, through which neutrophils extrude neutrophil extracellular traps to confine extracellular bacteria. Pyroptosis of cells infected with intracellular bacteria disrupts the niche for their replication. Furthermore, when undergoing GSDMD-mediated pyroptosis, infected macrophages can form pore-induced intracellular traps (PITs), which further help to restrain intracellular pathogens. Finally, the GSDM-dependent release of mediators is involved in eliciting and regulating local and potentially systemic inflammatory responses associated with infections. GSDM pore formation is a tightly regulated process during infection. Controlled activation can support battling an infection, whereas excessive activation can have detrimental effects. GSDM pores can also target bacterial walls, as described for GSDMB and GSDMD, with intracellular and extracellular pathogens, respectively. b, During the course of inflammatory bowel disease (IBD), GSDMs expressed in both epithelial and immune cells are pivotal in regulating inflammation. In intestinal epithelial cells (IECs), full-length (FL) GSDMB promotes epithelial repair. Conversely, GSDMD-FL mediates the release of IL-1β that fuels intestinal inflammation. Furthermore, GSDM-dependent pyroptosis of IECs is pathogenic in IBD, causing loss of mucosal integrity (by killing epithelial cells) and mediating the release of inflammatory mediators. Macrophage-derived cleaved GSDMD has an ambiguous role, described as both promoting and protecting from colitis. HMGB1, high-mobility group box protein 1; sEVs, small extracellular vesicles.