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PreprintCited by 1Inflammasome and immune disordersCell death mechanisms and regulationImmune Response and Inflammation

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Caspase-1 activates gasdermin A in non-mammals

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Billman, Zachary P., Kovacs, Stephen B., Wei, Bo, Kang, Kidong, Cissé, Ousmane H., Miao, Edward A.·2024·eLife
DOI 10.7554/elife.92362.3

Preprint — published as 10.7554/elife.92362.4

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Abstract

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

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Metadata

Authors
Billman, Z. P., Kovacs, S. B., Wei, B., Kang, K., Cissé, O. H., & Miao, E. A.
Affiliations
  • University of North Carolina at Chapel Hill (US)
  • Duke University (US)
  • National Institutes of Health (US)
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2024-02-19
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.92362.3
OpenAlex
W4391988564
Cited by
1
References
3
Citations by year
2024: 1
Type
posted content
Language
en
Open access
Licence
Locations
eLife (acceptedVersion, cc-by)
Funders
National Institutes of Health (AI133236, AI139304, AI136920, AI148302, AI175078, AR072694)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords
caspase-1, GSDMA, gasdermin D, gasdermin E, pyroptosis, protein evolution, gene duplication, amphibians, reptiles, birds, mammals

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