研究揭示梭菌毒素受體特異性的分子基礎
作者：
小柯機器人發布時間：2020/6/28 13:56:51
加拿大多倫多大學Mikko Taipale、加拿大病童醫院Roman A. Melnyk和Jean-Philippe Julien研究小組合作發現，索氏梭菌致死毒素（TcsL）識別軸突向蛋白揭示了梭菌毒素受體特異性的原理。相關論文於2020年6月25日在線發表於《細胞》雜誌。
利用CRISPR / Cas9篩選，研究人員發現軸突向蛋白SEMA6A和SEMA6B是TcsL的受體。研究人員發現重組SEMA6A可以保護小鼠免受TcsL導致的水腫。3.3Å冷凍電鏡結構表明TcsL與SEMA6A的結合區域與TcdB中與結構無關捲曲蛋白結合的區域相同。值得注意的是，處在不同進化面上的15個突變足以將TcsL的結合特異性區域轉換為TcdB的結合特異性區域。該發現表明軸突向蛋白是TcsL生理相關的受體，並揭示了高度相關毒素之間組織靶向和發病機制差異的分子基礎。
據介紹，致病性梭菌屬細菌會分泌強效毒素，其可誘導嚴重的宿主組織損傷。TcsL可誘發與致命性婦科感染相關的中毒性休克綜合症。TcsL與艱難梭菌TcdB相似，後者通過結腸上皮細胞的捲曲受體進入宿主細胞。然而，索氏梭菌感染靶向血管內皮細胞，這表明TcsL利用了另一種受體。
附：英文原文
Title: Recognition of Semaphorin Proteins by P. sordellii Lethal Toxin Reveals Principles of Receptor Specificity in Clostridial Toxins
Author: Hunsang Lee, Greg L. Beilhartz, Iga Kucharska, Swetha Raman, Hong Cui, Mandy Hiu Yi Lam, Huazhu Liang, John L. Rubinstein, Daniel Schramek, Jean-Philippe Julien, Roman A. Melnyk, Mikko Taipale
Issue&Volume: 2020-06-25
Abstract: 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 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.
DOI: 10.1016/j.cell.2020.06.005
Source: https://www.cell.com/cell/fulltext/S0092-8674(20)30692-9
Cell：《細胞》，創刊於1974年。隸屬於細胞出版社，最新IF：36.216