The enigmatic roles of epithelial gasdermin B: Recent discoveries and controversies

The role of gasdermin B (GSDMB) as an executioner of pyroptosis in intestinal epithelial cells is controversial, with emerging evidence supporting its role in alternative activities that go beyond pyroptotic cell death. Recent findings regarding GSDMB's function during gastrointestinal disorders suggest an overall protective role of epithelium-derived GSDMB, promoting pyroptosis of cancer cells, bactericidal processes, and epithelial restitution and wound repair. Several mechanisms for controlling GSDMB function exist, and at different levels (e.g., as a consequence of GSDMB polymorphisms, by alternative splicing, and through regulation of its cleavage, among others). We are at the advent of discovery regarding GSDMB's biology, with recent studies providing important insights into the mechanism(s) of such regulation and its specific roles during health and disease states. Gasdermin B (GSDMB) belongs to a family of structurally related proteins [(i.e., gasdermins (GSDMs)]. It distinguishes itself from other members by the lack of autoinhibition but clear bioactivity of its full-length form, its preference to bind to phosphatidylinositol phosphates and sulfatides, and the ability to promote both lytic and nonlytic cellular functions. It is the only gasdermin that lacks a mouse ortholog, making in vivo mechanistic studies challenging to perform. GSDMB is abundantly expressed in epithelial cells lining organs that directly interface with the external environment, such as the gastrointestinal tract, with emerging evidence supporting its role in enteric infections, inflammatory bowel disease (IBD), and colorectal cancer. This review discusses the unique features of GSDMB among other gasdermin family members and controversies surrounding GSDMB-dependent mammalian inflammatory cell death (i.e., pyroptosis), including recent discoveries revealing both lytic and nonlytic functions of epithelial-derived GSDMB, particularly during gut health and disease. Gasdermin B (GSDMB) belongs to a family of structurally related proteins [(i.e., gasdermins (GSDMs)]. It distinguishes itself from other members by the lack of autoinhibition but clear bioactivity of its full-length form, its preference to bind to phosphatidylinositol phosphates and sulfatides, and the ability to promote both lytic and nonlytic cellular functions. It is the only gasdermin that lacks a mouse ortholog, making in vivo mechanistic studies challenging to perform. GSDMB is abundantly expressed in epithelial cells lining organs that directly interface with the external environment, such as the gastrointestinal tract, with emerging evidence supporting its role in enteric infections, inflammatory bowel disease (IBD), and colorectal cancer. This review discusses the unique features of GSDMB among other gasdermin family members and controversies surrounding GSDMB-dependent mammalian inflammatory cell death (i.e., pyroptosis), including recent discoveries revealing both lytic and nonlytic functions of epithelial-derived GSDMB, particularly during gut health and disease.