Shigella ubiquitin ligase IpaH7.8 targets gasdermin D for degradation to prevent pyroptosis and enable infection.

Autor:	Luchetti G; Department of Physiological Chemistry, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA., Roncaioli JL; Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, Berkeley CA 94720, USA., Chavez RA; Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, Berkeley CA 94720, USA., Schubert AF; Department of Structural Biology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA., Kofoed EM; Department of Immunology and Infectious Diseases, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA., Reja R; Department of Oncology Bioinformatics, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA., Cheung TK; Department of Microchemistry, Proteomics, and Lipidomics, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA., Liang Y; Department of Microchemistry, Proteomics, and Lipidomics, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA., Webster JD; Department of Pathology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA., Lehoux I; Department of Biomolecular Resources, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA., Skippington E; Department of OMNI Bioinformatics, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA., Reeder J; Department of OMNI Bioinformatics, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA., Haley B; Department of Molecular Biology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA., Tan MW; Department of Immunology and Infectious Diseases, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA., Rose CM; Department of Microchemistry, Proteomics, and Lipidomics, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA., Newton K; Department of Physiological Chemistry, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA., Kayagaki N; Department of Physiological Chemistry, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA., Vance RE; Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, Berkeley CA 94720, USA; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley CA 94720, USA., Dixit VM; Department of Physiological Chemistry, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: dixit@gene.com.
Jazyk:	angličtina
Zdroj:	Cell host & microbe [Cell Host Microbe] 2021 Oct 13; Vol. 29 (10), pp. 1521-1530.e10. Date of Electronic Publication: 2021 Sep 06.
DOI:	10.1016/j.chom.2021.08.010
Abstrakt:	The pore-forming protein gasdermin D (GSDMD) executes lytic cell death called pyroptosis to eliminate the replicative niche of intracellular pathogens. Evolution favors pathogens that circumvent this host defense mechanism. Here, we show that the Shigella ubiquitin ligase IpaH7.8 functions as an inhibitor of GSDMD. Shigella is an enteroinvasive bacterium that causes hemorrhagic gastroenteritis in primates, but not rodents. IpaH7.8 contributes to species specificity by ubiquitinating human, but not mouse, GSDMD and targeting it for proteasomal degradation. Accordingly, infection of human epithelial cells with IpaH7.8-deficient Shigella flexneri results in increased GSDMD-dependent cell death compared with wild type. Consistent with pyroptosis contributing to murine disease resistance, eliminating GSDMD from NLRC4-deficient mice, which are already sensitized to oral infection with Shigella flexneri, leads to further enhanced bacterial replication and increased disease severity. This work highlights a species-specific pathogen arms race focused on maintenance of host cell viability. Competing Interests: Declaration of interests All authors except J.R., R.A.C., and R.E.V. are employees of Genentech. R.E.V. is an investigator of the Howard Hughes Medical Institute and a consultant for Ventus Therapeutics and Tempest Therapeutics. (Copyright © 2021 Genentech. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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