Emam Elhassan Ali Fathi, Singh Devendra Pratap, Saini Deepak K, Varshney Umesh
Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India.
Developmental Biology and Genetics, Indian Institute of Science, Bangalore 560012, India.
Nucleic Acids Res. 2025 Aug 27;53(16). doi: 10.1093/nar/gkaf842.
Bacterial pathogens such as Mycobacterium tuberculosis majorly rely on two-component signaling (TCS) systems to sense and generate adaptive responses to the dynamic and stressful host environment. TCS comprises a sensor histidine kinase (SHK) that perceives the environmental signal and a response regulator (RR) that modulates the target gene expression. TCS occurs via a phosphotransfer event from SHK to RR. However, the mechanisms that regulate phosphotransfer events are not well understood. We explored the role of MutT1, originally characterized to hydrolyze oxidized GTP (8-oxo-GTP) and dGTP (8-oxo-dGTP), in TCS regulation. Unlike other MutT proteins, mycobacterial MutT1 comprises two domains (N-terminal domain, NTD; and C-terminal domain, CTD). Structurally, MutT1 NTD is like MutT proteins in other organisms. However, the MutT1 CTD is similar to Escherichia coli SixA, a histidine phosphatase with an Arg-His-Gly (RHG) motif. We show that MutT1 CTD dephosphorylates many SHKs and impacts expression of their target genes, highlighting the role of MutT1 in regulating TCS. These novel findings are of special significance because they provide us with an extrinsic phosphatase mechanism to reset TCS signaling. The study reveals an intricate interplay between an enzyme that sanitizes the cellular nucleotide pool and bacterial signaling pathways, offering insights into the adaptation mechanisms.
结核分枝杆菌等细菌病原体主要依靠双组分信号传导（TCS）系统来感知动态且充满压力的宿主环境，并产生适应性反应。TCS由感知环境信号的传感器组氨酸激酶（SHK）和调节靶基因表达的反应调节因子（RR）组成。TCS通过从SHK到RR的磷酸转移事件发生。然而，调节磷酸转移事件的机制尚不清楚。我们探究了最初被鉴定为水解氧化型GTP（8-氧代-GTP）和dGTP（8-氧代-dGTP）的MutT1在TCS调节中的作用。与其他MutT蛋白不同，分枝杆菌MutT1包含两个结构域（N端结构域，NTD；和C端结构域，CTD）。在结构上，MutT1 NTD与其他生物体中的MutT蛋白相似。然而，MutT1 CTD与大肠杆菌SixA相似，SixA是一种具有精氨酸-组氨酸-甘氨酸（RHG）基序的组氨酸磷酸酶。我们发现MutT1 CTD可使许多SHK去磷酸化，并影响其靶基因的表达，突出了MutT1在调节TCS中的作用。这些新发现具有特殊意义，因为它们为我们提供了一种重置TCS信号传导的外在磷酸酶机制。该研究揭示了一种净化细胞核苷酸库的酶与细菌信号通路之间复杂的相互作用，为适应机制提供了见解。
