Journal
CELL HOST & MICROBE
Volume 29, Issue 10, Pages 1521-+Publisher
CELL PRESS
DOI: 10.1016/j.chom.2021.08.010
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Funding
- Genentech
- NIH [AI075039, AI063302, AI155634]
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The study reveals the mechanism by which IpaH7.8 from Shigella ubiquitinates human GSDMD and targets it for proteasomal degradation, contributing to the bacterium's impact on humans rather than mice.
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.
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