Journal
CELL
Volume 184, Issue 12, Pages 3178-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2021.04.036
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Funding
- National Institutes of Health [AI083359, 5T32AI007520]
- Welch Foundation [I-1704]
- Burroughs Welcome Fund [1011019]
- Howard Hughes Medical Institute
- Simons Foundation Faculty Scholars Program [55108499]
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GSDMB is targeted and destroyed by the IpaH7.8 effector protein secreted by Shigella flexneri, protecting the bacterium from natural killer cells. Unlike other gasdermin family members, GSDMB exhibits direct microbiocidal activity by recognizing phospholipids found on Gram-negative bacterial membranes.
Gasdermin B (GSDMB) belongs to a large family of pore-forming cytolysins that execute inflammatory cell death programs. While genetic studies have linked GSDMB polymorphisms to human disease, its function in the immunological response to pathogens remains poorly understood. Here, we report a dynamic host-pathogen conflict between GSDMB and the IpaH7.8 effector protein secreted by enteroinvasive Shigella flexneri. We show that IpaH7.8 ubiquitinates and targets GSDMB for 26S proteasome destruction. This virulence strategy protects Shigella from the bacteriocidic activity of natural killer cells by suppressing granzyme-A-mediated activation of GSDMB. In contrast to the canonical function of most gasdermin family members, GSDMB does not inhibit Shigella by lysing host cells. Rather, it exhibits direct microbiocidal activity through recognition of phospholipids found on Gram-negative bacterialmembranes. These findings place GSDMB as a central executioner of intracellular bacterial killing and reveal a mechanism employed by pathogens to counteract this host defense system.
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