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Direct binding of polymeric GBP1 to LPS disrupts bacterial cell envelope functions.
The EMBO Journal ( IF 11.4 ) Pub Date : 2020-06-08 , DOI: 10.15252/embj.2020104926
Miriam Kutsch 1 , Linda Sistemich 2 , Cammie F Lesser 3, 4 , Marcia B Goldberg 3, 4 , Christian Herrmann 2 , Jörn Coers 1, 5
Affiliation  

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.

中文翻译:

聚合物GBP1与LPS的直接结合会破坏细菌细胞的包膜功能。

在革兰氏阴性细菌的外膜中,脂多糖(LPS)的O抗原片段形成化学机械屏障,而脂质A部分锚定LPS分子。感染后,人鸟苷酸结合蛋白-1(hGBP1)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传感器胱天蛋白酶-4的活化,并阻止肌动蛋白驱动的肠道病原菌志贺氏菌传播。hGBP1的多种抗菌功能的潜在分子机制尚不清楚。在这里,我们证明hGBP1直接与LPS结合并通过蛋白质聚合诱导“类似洗涤剂”的LPS聚集。聚合的hGBP1与细菌表面的结合破坏了O抗原屏障,从而掩盖了脂质A,引起caspase-4募集,增强了多粘菌素B的抗菌活性,并阻止了志贺氏菌外膜肌动蛋白运动因子IcsA的功能。这些发现将hGBP1表征为可与LPS结合的表面活性剂,它破坏了外膜的刚性,从而对革兰氏阴性细菌细胞包膜的功能发挥了多效性作用。
更新日期:2020-07-01
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