Nature2014-06-27 2:30 PM

抗菌蛋白的作用机制 Antibacterial membrane attack by a pore-forming intestinal C-type lectin

论文摘要 

Reg 蛋白是一组C-型外源凝集素,是由与外部环境中的细菌直接接触的器官分泌的。RegIIIRR是这一蛋白家族的一员,与细菌表面糖结合,杀死其细菌目标,以针对可能会导致败血症的组织入侵提供保护。这项研究详细说明了由两个步骤组成的一个过程。在此过程中,杀菌是由人C-型外源凝集素RegIIIR完成的,后者能杀灭格兰氏阳性细菌。该外源凝集素首先与细菌肽聚糖结合,然后在膜上发生寡聚,形成一个“透化孔”;该“透化孔”在细菌膜上打出一个洞,最终通过“渗透性溶解”将细菌杀灭。

Abstract 

Human body-surface epithelia coexist in close association with complex bacterial communities and are protected by a variety of antibacterial proteins. C-type lectins of the RegIII family are bactericidal proteins that limit direct contact between bacteria and the intestinal epithelium and thus promote tolerance to the intestinal microbiota. RegIII lectins recognize their bacterial targets by binding peptidoglycan carbohydrate, but the mechanism by which they kill bacteria is unknown. Here we elucidate the mechanistic basis for RegIII bactericidal activity. We show that human RegIIIα (also known as HIP/PAP) binds membrane phospholipids and kills bacteria by forming a hexameric membrane-permeabilizing oligomeric pore. We derive a three-dimensional model of the RegIIIα pore by docking the RegIIIα crystal structure into a cryo-electron microscopic map of the pore complex, and show that the model accords with experimentally determined properties of the pore. Lipopolysaccharide inhibits RegIIIα pore-forming activity, explaining why RegIIIα is bactericidal for Gram-positive but not Gram-negative bacteria. Our findings identify C-type lectins as mediators of membrane attack in the mucosal immune system, and provide detailed insight into an antibacterial mechanism that promotes mutualism with the resident microbiota.

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