Gasdermins: multifunctional effectors of membrane permeabilization across cellular compartments

Members of the gasdermin (GSDM) family are pore-forming proteins primarily known for executing inflammatory cell death known as pyroptosis. GSDM-mediated pore formation at the plasma membrane (PM) facilitates the selective secretion of immunomodulatory proteins and nonselective ionic fluxes during pyroptotic signaling. Recent findings suggest that GSDMs also modulate intracellular processes by associating with and altering membranes in various organelles, including mitochondria, lysosomes, endoplasmic reticulum (ER), and the nucleus. These activities may trigger alternative signaling pathways that do not necessarily involve PM perforation. In this review, we explore the diverse mechanisms of GSDM association across organelle membranes and discuss the physiological and pathological implications of GSDM-induced membrane integrity alteration.