Ruiz Nestor, Hendrixson David R
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9048.
Proc Natl Acad Sci U S A. 2025 Sep 30;122(39):e2512446122. doi: 10.1073/pnas.2512446122. Epub 2025 Sep 25.
Canonical bacterial two-component signal transduction systems (TCSs) detect cues by sensors with opposing kinase and phosphatase activities to alter the level of phosphorylation of cognate response regulators to mediate responses. We previously identified the BumSR TCS as the founding member of a bacterial TCS family in which the sensor solely functions as a phosphatase. Sensing specific intestinal metabolites inhibits BumS dephosphorylation of phospho-BumR (P-BumR) to impact BumR as a transcriptional regulator of genes influencing host colonization. Since BumS lacks kinase activity, BumR must depend upon a noncognate phosphodonor in the bacterium to form P-BumR. Through a genetic screen and selection, physiological assays, and biochemical analysis, we identified acetyl phosphate (AcP) and carbamoyl phosphate (CP) as natural in vivo phosphodonors for BumR. In , AcP and CP are products of metabolic pathways fueled by amino acids favored by the bacterium as carbon sources for growth. Producing and utilizing AcP and CP as bona fide BumR phosphodonors allows BumSR to integrate different types of inputs for signal transduction. Microbiota-generated gut metabolites are cues for BumS to control its phosphatase activity for P-BumR and inform about the spatial location of in host intestines. In contrast, AcP and CP are cues for BumR that directly influence P-BumR levels and activity and inform about the richness of favored carbon sources in intestinal niches for optimal energy generation and metabolism. Our study reveals how a bacterial TCS strategically integrates information from multiple cues through both essential components for optimal signal transduction.
典型的细菌双组分信号转导系统（TCSs）通过具有相反激酶和磷酸酶活性的传感器来检测信号，以改变同源应答调节因子的磷酸化水平来介导反应。我们之前将BumSR TCS鉴定为细菌TCS家族的创始成员，其中该传感器仅作为磷酸酶发挥作用。感知特定的肠道代谢产物会抑制磷酸化BumR（P-BumR）的BumS去磷酸化，从而影响BumR作为影响宿主定殖基因的转录调节因子。由于BumS缺乏激酶活性，BumR必须依赖细菌中的非同源磷酸供体来形成P-BumR。通过遗传筛选和选择、生理学分析以及生化分析，我们确定乙酰磷酸（AcP）和氨基甲酰磷酸（CP）是BumR在体内的天然磷酸供体。在体内，AcP和CP是由细菌偏爱的氨基酸作为生长碳源所驱动的代谢途径的产物。将AcP和CP作为真正的BumR磷酸供体进行产生和利用，使得BumSR能够整合不同类型的输入信号用于信号转导。微生物群产生的肠道代谢产物是BumS控制其对P-BumR磷酸酶活性的信号，并告知宿主肠道中细菌的空间位置。相比之下，AcP和CP是BumR的信号，它们直接影响P-BumR的水平和活性，并告知肠道生态位中有利于最佳能量产生和代谢的碳源丰富程度。我们的研究揭示了细菌TCS如何通过两个关键组分从多个信号中战略性地整合信息以实现最佳信号转导。
