Cell
Volume 182, Issue 2, 23 July 2020, Pages 345-356.e16
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Article
Recognition of Semaphorin Proteins by P. sordellii Lethal Toxin Reveals Principles of Receptor Specificity in Clostridial Toxins

https://doi.org/10.1016/j.cell.2020.06.005Get rights and content
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Highlights

  • CRISPR screen identifies SEMA6A and SEMA6B as receptors for P. sordellii lethal toxin TcsL

  • Soluble SEMA6A ectodomain protects mouse lungs from TcsL-induced edema

  • 3.3 Å cryo-EM structure of TcsL bound to SEMA6A reveals atomic details of the interaction

  • 15 mutations in the TcsL receptor-binding interface rewire receptor specificity

Summary

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 Å 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.

Keywords

bacterial exotoxins
Clostridial toxins
P. sordellii
TcsL
CRISPR/Cas9 screening
semaphorin
SEMA6A
SEMA6B
cryo-EM

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