Direct binding of polymeric GBP1 to LPS disrupts bacterial cell envelope functions
Direct binding of polymeric GBP1 to LPS disrupts bacterial cell envelope functions
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DOI：
10.15252/embj.2020104926
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发表时间：
2020-06-08
期刊：
影响因子：
11.4
通讯作者：
Coers, Jorn
中科院分区：
文献类型：
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作者：
Kutsch, Miriam;Sistemich, Linda;Coers, Jorn
在革兰氏阴性菌的外膜中，脂多糖（LPS）的O-抗原片段形成化学机械屏障，而脂质A部分锚LPS分子。感染后，人鸟苷酸结合蛋白-1（hGBP 1）与细胞内革兰氏阴性细菌病原体共定位，促进细菌杀灭，促进脂质A传感器半胱天冬酶-4的激活，并阻断肌动蛋白驱动的肠道病原体志贺氏菌的传播。hGBP 1多种抗菌功能的潜在分子机制尚不清楚。在这里，我们证明，hGBP 1直接结合到LPS和诱导“洗涤剂样”LPS集群通过蛋白质聚合。聚合的hGBP 1与细菌表面的结合破坏了O-抗原屏障，从而暴露了脂质A，引发半胱天冬酶-4募集，增强了多粘菌素B的抗菌活性，并阻断了志贺氏菌外膜肌动蛋白运动因子IcsA的功能。这些发现将hGBP 1表征为LPS结合表面活性剂，其使外膜的刚性不稳定，从而对革兰氏阴性细菌细胞包膜的功能发挥多效性作用。
In the outer membrane of gram-negative bacteria, O-antigen segments of lipopolysaccharide (LPS) form a chemomechanical barrier, whereas lipid A moieties anchor LPS molecules. Upon infection, human guanylate binding protein-1 (hGBP1) colocalizes with intracellular gram-negative bacterial pathogens, facilitates bacterial killing, promotes activation of the lipid A sensor caspase-4, and blocks actin-driven dissemination of the enteric pathogen Shigella. The underlying molecular mechanism for hGBP1's diverse antimicrobial functions is unknown. Here, we demonstrate that hGBP1 binds directly to LPS and induces "detergent-like" LPS clustering through protein polymerization. Binding of polymerizing hGBP1 to the bacterial surface disrupts the O-antigen barrier, thereby unmasking lipid A, eliciting caspase-4 recruitment, enhancing antibacterial activity of polymyxin B, and blocking the function of the Shigella outer membrane actin motility factor IcsA. These findings characterize hGBP1 as an LPS-binding surfactant that destabilizes the rigidity of the outer membrane to exert pleiotropic effects on the functionality of gram-negative bacterial cell envelopes.