Journal
CELL
Volume 182, Issue 2, Pages 345-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2020.06.005
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Funding
- University of Toronto's Medicine by Design initiative (MbD New Ideas Award)
- University of Toronto's Medicine by Design initiative (MbD Postdoctoral fellowship)
- Canada First Research Excellence Fund (CFREF)
- Krembil Award
- CIHR [RN292258 -366017]
- NSERC [RGPIN-2017-06817]
- CIFAR Azrieli Global Scholar program
- Ontario Early Researcher Awards program
- Canada Research Chairs program
- Canada Foundation for Innovation
- Ontario Research Fund
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Pathogenic clostridial species secrete potent toxins that induce severe host tissue damage. Paeniclostridium sordellii lethal toxin (TcsL) causes an almost invariably lethal toxic shock syndrome associated with gynecological infections. TcsL is 87% similar to C. difficile TcdB, which enters host cells via Frizzled receptors in colon epithelium. However, P. sordellii infections target vascular endothelium, suggesting that TcsL exploits another receptor. Here, using CRISPR/Cas9 screening, we establish semaphorins SEMA6A and SEMA6B as TcsL receptors. We demonstrate that recombinant SEMA6A can protect mice from TcsL-induced edema. A 3.3 angstrom cryo-EM structure shows that TcsL binds SEMA6A with the same region that in TcdB binds structurally unrelated Frizzled. Remarkably, 15 mutations in this evolutionarily divergent surface are sufficient to switch binding specificity of TcsL to that of TcdB. Our findings establish semaphorins as physiologically relevant receptors for TcsL and reveal the molecular basis for the difference in tissue targeting and disease pathogenesis between highly related toxins.
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