化学蛋白质组学分析揭示细菌胆汁酸耐受机制,ACS Chemical Biology

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化学蛋白质组学分析揭示细菌胆汁酸耐受机制
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2022-09-01 , DOI: 10.1021/acschembio.2c00286
Biwei Liu ₁ , Shentian Zhuang ₁ , Runze Tian ₁ , Yuan Liu ₂ , Yanqi Wang ₁ , Xiaoguang Lei _{1,

2} , Chu Wang _{1,

2}

Affiliation

胆汁酸 (BAs) 是一类具有重要功能的内源性代谢产物。作为两亲性分子，BA 具有很强的抗菌作用，可防止肠道微生物群过度生长并防御病原体的入侵。然而，一些致病病原体可以在 BA 压力下存活，并且关于它们如何发展 BA 耐受性的知识有限。在这项工作中，我们应用定量化学蛋白质组学策略来分析细菌中与 BA 相互作用的蛋白质，旨在发现 BA 的传感途径。使用具有定量质谱法的可点击和照片亲和 BA 探针，我们确定了细菌中双组分系统 (TCS) 的组氨酸激酶 (HK) 列表作为 BA 的新结合靶点。基因筛选显示敲除一种特定的 HK，EnvZ，使细菌对 BA 具有显着的敏感性。进一步的生化和遗传实验表明，BA 与 EnvZ 中的特定口袋结合并激活下游信号通路以帮助 BA 从细菌中流出，从而产生 BA 耐受性。总的来说，我们的数据显示 EnvZ 是细菌中 BA 的新型传感器，其相关的 TCS 信号通路在介导细菌 BA 耐受性方面起着关键作用，这为对抗 BA 耐受性病原体开辟了新的机会。

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Chemoproteomic Profiling Reveals the Mechanism of Bile Acid Tolerance in Bacteria

Bile acids (BAs) are a class of endogenous metabolites with important functions. As amphipathic molecules, BAs have strong antibacterial effects, preventing overgrowth of the gut microbiota and defending the invasion of pathogens. However, some disease-causing pathogens can survive the BA stress and knowledge is limited about how they develop BA tolerance. In this work, we applied a quantitative chemoproteomic strategy to profile BA-interacting proteins in bacteria, aiming to discover the sensing pathway of BAs. Using a clickable and photo-affinity BA probe with quantitative mass spectrometry, we identified a list of histidine kinases (HKs) of the two-component systems (TCS) in bacteria as the novel binding targets of BA. Genetic screening revealed that knocking out one specific HK, EnvZ, renders bacteria with significant sensitivity to BA. Further biochemical and genetic experiments demonstrated that BA binds to a specific pocket in EnvZ and activates a downstream signaling pathway to help efflux of BA from bacteria, resulting in BA tolerance. Collectively, our data revealed that EnvZ is a novel sensor of BA in bacteria and its associated TCS signaling pathway plays a critical role in mediating bacterial BA tolerance, which opens new opportunities to combat BA-tolerating pathogens.

更新日期：2022-09-01

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