Caspase-1 activates gasdermin A in non-mammals

• DOI: 10.7554/elife.92362
• Publication Date: 2023-11-22T11:23:07Z
• Authors: Zachary Paul Billman; Stephen Bela Kovacs; Bo Wei; Kidong Kang; Ousmane H Cissé; Edward A Miao
• Keywords: Pyroptosis; NLRP1; Furin; Caspase 2

Gasdermins oligomerize to form pores in the cell membrane, causing regulated lytic death called pyroptosis. Mammals encode five gasdermins that can trigger pyroptosis: GSDMA, B, C, D, and E. Caspase granzyme proteases cleave linker regions of activate GSDMB, E, but no endogenous activation pathways are yet known for GSDMA. Here, we perform a comprehensive evolutionary analysis gasdermin family. A gene duplication GSDMA common ancestor caecilian amphibians, reptiles, birds gave rise GSDMA–D mammals. Uniquely our tree, amphibian, reptile, bird group separate clade than mammal Remarkably, numerous species contain caspase-1 cleavage sites like YVAD or FASD linker. We show from birds, reptiles all cleaved by caspase-1. Thus, was originally host-encoded protease In mammals site is disrupted; instead, new protein, GSDMD, target Mammal uses exosite interactions with GSDMD C-terminal domain confer specificity this interaction, whereas stereotypical tetrapeptide sequence Our results reveal an evolutionarily stable association between family, albeit shifting one. Caspase-1 repeatedly changes its over time at speciation junctures, initially cleaving GSDME fish, then amphibians/reptiles/birds, finally