Theme and variations: activation and regulation of gasdermin-mediated inflammation

Gasdermins are effectors for pyroptosis, a highly inflammatory form of cell death. Mammalian gasdermin (GSDM) family members harbor N-terminal domains (NTDs) that bind membrane phospholipids and assemble oligomeric pores. Their C-terminal domains are regulatory modules, which suppress the cytolytic function of the NTDs under homeostatic conditions, and in several cases mediate the recruitment of proteases that cleave GSDMs following upstream signaling. The initial model for gasdermin activation was that upon protease processing their NTDs localize to the plasma membrane to assemble oligomeric pores and mediate pyroptosis. Emerging evidence suggests fascinating variations of this paradigm. For example, cleavage-independent pyroptotic activities have been reported for several family members that undergo post-translational modifications such as S-acylation, PARylation, oxidation, or phosphorylation. Furthermore, some gasdermins associate with membranes from organelles such as mitochondria, and often play non-pyroptotic roles in cellular physiology. In the present mini-review, we briefly summarize the molecular mechanisms governing the activation of different gasdermin family members, focusing on protease processing as the most well-studied mechanism. This is followed by discussion of two aspects of gasdermin biology. Namely, cleavage-independent pyroptotic activities and the localization of gasdermins at mitochondria and nucleus implicated in pyroptotic and non-pyroptotic functions. The diverse mechanisms of gasdermin activation and regulation in response to different upstream signaling pathways demonstrate the versatility of this conserved family of pore-forming proteins in various aspects of cellular physiology throughout evolution. The pleiotropic functions of gasdermins in inflammatory disorders, antimicrobial defense, antitumor immunity, neurodegenerative disorders etc., suggest fertile ground for exploration of therapeutic avenues.