沈锡辉、张磊等《Nature Communications》2022年

论文题目：Autoinducer-2 and bile salts induce c-di-GMP synthesis to repress the T3SS via a T3SS chaperone

论文作者：Shuyu Li, Hengxi Sun, Jianghan Li, Yujiao Zhao, Ruiying Wang, Lei Xu, Chongyi Duan, Jialin Li, Zhuo Wang, Qinmeng Liu, Yao Wang, Songying Ouyang, Xihui Shen & Lei Zhang

论文摘要：Cyclic di-GMP (c-di-GMP) transduces extracellular stimuli into intracellular responses, coordinating a plethora of important biological processes. Low levels of c-di-GMP are often associated with highly virulent behavior that depends on the type III secretion system (T3SS) effectors encoded, whereas elevated levels of c-di-GMP lead to the repression of T3SSs. However, extracellular signals that modulate c-di-GMP metabolism to control T3SSs and c-di-GMP effectors that relay environmental stimuli to changes in T3SS activity remain largely obscure. Here, we show that the quorum sensing signal autoinducer-2 (AI-2) induces c-di-GMP synthesis via a GAPES1 domain-containing diguanylate cyclase (DGC) YeaJ to repress T3SS-1 gene expression in Salmonella enterica serovar Typhimurium. YeaJ homologs capable of sensing AI-2 are present in many other species belonging to Enterobacterales. We also reveal that taurocholate and taurodeoxycholate bind to the sensory domain of the DGC YedQ to induce intracellular accumulation of c-di-GMP, thus repressing the expression of T3SS-1 genes. Further, we find that c-di-GMP negatively controls the function of T3SSs through binding to the widely conserved CesD/SycD/LcrH family of T3SS chaperones. Our results support a model in which bacteria sense changes in population density and host-derived cues to regulate c-di-GMP synthesis, thereby modulating the activity of T3SSs via a c-di-GMP-responsive T3SS chaperone.

环二鸟苷单磷酸(c-di-GMP)是细菌中广泛存在的一类核苷类第二信使，能够调控细菌的生物被膜形成、胞外多糖产生、运动性、黏附以及毒力等众多生理和病理过程。III型分泌系统(T3SSs)是大多数革兰氏阴性病原细菌感染宿主的重要武器。病原菌通过T3SSs将一系列效应蛋白注入宿主细胞内，逃避宿主细胞的免疫防御并建立感染。T3SSs基因的表达受各种环境和宿主因素的影响，也受到c-di-GMP信号途径的调控，但具体分子机制尚不清楚。本研究发现群体感应信号分子AI-2通过作用于具GAPES1结构域的跨膜二鸟苷酸环化酶YeaJ促进沙门氏菌胞内c-di-GMP水平的提升，从而抑制其T3SS-1基因的表达。我们还发现肠道胆汁酸盐组分牛磺胆酸盐和牛磺脱氧胆酸盐作用于跨膜二鸟苷酸环化酶YedQ，刺激沙门氏菌胞内c-di-GMP合成，也能抑制其T3SS-1基因表达。进一步我们发现c-di-GMP通过作用于沙门氏菌T3SS-1的CesD/SycD/LcrH家族伴侣蛋白SicA抑制T3SS-1基因表达，且发现许多其他革兰氏阴性病原菌（肠出血性大肠埃希杆菌、铜绿假单胞菌、弗氏志贺菌、小肠结肠炎耶尔森氏菌、泰国伯克霍尔德菌、副溶血性弧菌等）中该家族的T3SS伴侣蛋白也是c-di-GMP的作用靶标。本研究揭示了c-di-GMP通过保守的分子机制来调控病原细菌T3SSs的活性，丰富了对c-di-GMP信号代谢、受体感应及调控机制的认知，同时为抗细菌感染药物研发提供了新靶点。

文章链接：https://www.nature.com/articles/s41467-022-34607-9