Elucidating the structural mechanism of pore formation by the (GSDM) Gasdermin family

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Gasdermins (GSDMs) represent a family of related proteins that caught the attention of the field recently with fascinating biology. The GSDM family comprises six members in human (GSDMA, GSMDB, GSDMC, GSDMD, GSDME/DFNA5, and DFNB59), and in mouse, three forms of GSDMA are present, GSDMA1-3. Recently, GSDMD was identified as a downstream effector of inflammasomes, which are supramolecular complexes that activate inflammatory caspases (-1, -4 and -5 in human and - 1 and -11 in mouse). GSDMD gets cleaved by caspases to generate an N-terminal fragment (GSDMD- NT) and a C-terminal fragment (GSDMD-CT). GSDMD-NT mediates pyroptosis, a lytic cell death involving spillage of cellular contents, as well as secretion of the IL-1β cytokine, which is processed by caspase-1 to the mature form. We and others found that upon cleavage by inflammatory caspases, GSDMD-NT specifically binds to phosphatidylinositol phosphates (PIPs), phosphatidic acid (PA), phosphatidylserine (PS) and cardiolipin, and exhibits strong membrane-disrupting cytotoxicity in mammalian cells by forming pores on membranes during pyroptosis and in vitro. Other GSDMs are insensitive to inflammatory caspases. GSDME (also known as DFNA5) was shown to be activated by apoptotic caspases (-3 and -7), which also specifically block pyroptosis by cleaving GSDMD at a distinct site from the inflammatory caspases to inactivate the protein. Similar to apoptotic caspases, Enterovirus 71 (EV71) viral protease 3C cleaves GSDMD at a distinct site to inactivate it and to inhibit virus-induced pyroptosis. The activating enzymes for the remaining GSDMs remain to be discovered. Importantly, GSDMs, which are expressed in a variety of tissues, appear to exhibit a universal pore formation activity in vitro, suggesting that they each mediate lytic cell death under different physiological and pathological contexts. Here we propose to elucidate the structural mechanism of pore formation by the GSDM family; understanding how GSDMD and other gasdermin proteins are regulated and exert their pore forming activity will not only provide new insights on gasdermin-mediated cell death including pyroptosis, but also afford new therapeutic strategies for treating inflammasome-related and gasdermin-related diseases.