Punching Holes in Cellular Membranes: Biology and Evolution of Gasdermins

The gasdermin (GSDM) family has evolved as six gene clusters (GSDMA–E and Pejvakin, PJVK), and GSDM proteins are characterized by a unique N-terminal domain (N-GSDM). With the exception of PJVK, the N-GSDM domain is capable of executing plasma membrane permeabilization. Depending on the cell death modality, several protease- and kinase-dependent mechanisms directly regulate the activity of GSDME and GSDMD, the two most widely expressed and best-studied GSDMs. We provide an overview of all GSDMs in terms of biological function, tissue expression, activation, regulation, and structure. In-depth phylogenetic analysis reveals that GSDM genes show many gene duplications and deletions, suggesting that strong evolutionary forces and a unique position of the PJVK gene are associated with the occurrence of complex inner-ear development in vertebrates. Gasdermins (GSDMs) consist of a cytotoxic N-terminal domain (N-GSDM) domain, a hinge region with conserved aspartate cleavage sites (GSDMD and -E), and a C-terminal domain (C-GSDM) regulatory domain. The particular combination of positive and negative regulatory mechanisms, and the restricted expression patterns of some GSDMs, might not only underlie the unique and discriminating operation of GSDMs in particular pathways (inactivation of GSDMB and -D following caspase-3 activation) and cellular contexts (GSDMD in epithelial cells, GSDMA in keratinocytes) but also represent mechanisms of redundancy.Several checkpoints control the cytotoxic function of p30 N-GSDM by specific proteolysis, phosphorylation, exosome formation.In addition to the plasma membrane, some N-GSDMs also target mitochondria (N-GSDMA, -D, and -E), nuclear envelope membranes and azurophylic granules (N-GSDMD), or peroxisomes (PJVK), suggesting involvement in intracellular processes beyond cell death.GSDM genes originate in the animal kingdom from an ancestral GSDME-like gene starting in the Cnidaria. A duplication event of this ancestral GSDME gene resulted in PJVK in the Vertebrata that is associated with the occurrence of the complex inner ear. GSDMA genes are present in reptiles, birds, and platypus, whereas the GSDMB, GSDMC, and GSDMD genes additionally evolved in placentals and mammals, although these are deleted or expanded in particular species, reflecting high evolutionary pressure.