Abstract
Gasdermin proteins form large membrane pores in human cells that release immune cytokines and induce lytic cell death. Gasdermin pore formation is triggered by caspase-mediated cleavage during inflammasome signaling and is critical for defense against pathogens and cancer. We discovered gasdermin homologs encoded in bacteria that defended against phages and executed cell death. Structures of bacterial gasdermins revealed a conserved pore-forming domain that was stabilized in the inactive state with a buried lipid modification. Bacterial gasdermins were activated by dedicated caspase-like proteases that catalyzed site-specific cleavage and the removal of an inhibitory C-terminal peptide. Release of autoinhibition induced the assembly of large and heterogeneous pores that disrupted membrane integrity. Thus, pyroptosis is an ancient form of regulated cell death shared between bacteria and animals.
| Original language | English |
|---|---|
| Pages (from-to) | 221-+ |
| Number of pages | 5 |
| Journal | Science |
| Volume | 375 |
| Issue number | 6577 |
| DOIs | |
| State | Published - 14 Jan 2022 |
Bibliographical note
Funding Information:This study was supported by the Pew Biomedical Scholars Program (P.J.K.), the Burroughs Wellcome Fund PATH award (P.J.K.), the Mathers Foundation (P.J.K.), the Parker Institute for Cancer Immunotherapy (P.J.K.), European Research Council grant ERC-CoG 681203 (R.S.), Israel Science Foundation grant ISF 296/ 21 (R.S.), the Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine (R.S.), the Minerva Foundation and Federal German Ministry for Education and Research (R.S.), the Knell Family Center for Microbiology (R.S.), the Yotam project and the Weizmann Institute Sustainability and Energy Research Initiative (R.S.), the Dr. Barry Sherman Institute for Medicinal Chemistry (R.S.), National Institute of Health Cancer Immunology training grant T32CA207021 (A.G.J.), a Life Science Research Foundation postdoctoral fellowship of the Open Philanthropy Project (A.G.J.), a Minerva Foundation postdoctoral fellowship (T.W.), and a Herchel Smith Graduate Research Fellowship (B.D.-L.).
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