Two-Component Signalling Systems of M. tuberculosis: Regulators of Pathogenicity and More

Agrawal, Ruchi; Narayan, Vignesh H.; Saini, Deepak Kumar

doi:10.1007/978-1-4614-9224-5_4

Cited by 5 publications

(11 citation statements)

References 117 publications

(149 reference statements)

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“…Of interest is the latter response at steady state. To obtain the steady-state response, we set the left-hand sides of eqns (7) and (9) to zero and solved the resulting system of algebraic non-linear equations in conjunction with eqns (4) and (6).…”

Section: Mathematical Modellingmentioning

confidence: 99%

“…The M. tuberculosis genome encodes 11 genetically paired TCSs, two orphan SKs and six orphan RR proteins [5]. Studies of the TB bacilli using transcriptional profiling and gene knockouts have revealed that TCSs play an important role in facilitating successful adaptation to diverse environmental conditions encountered within the host [2,6]. The mtrAB and prrAB genes encoding corresponding TCSs have been shown to be essential for survival [7,8], mprAB for persistence [9] and devRS for hypoxic adaptation [10,11].…”

Section: Introductionmentioning

confidence: 99%

“…The mtrAB and prrAB genes encoding corresponding TCSs have been shown to be essential for survival [7,8], mprAB for persistence [9] and devRS for hypoxic adaptation [10,11]. Furthermore, inactivation of the TCSs regX3-senX3, tcrXY, trcRS, phoPR or kdpDE affects the growth and/or virulence of M. tuberculosis in animal infection models [6,12].…”

Section: Introductionmentioning

confidence: 99%

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The two-component signalling networks of Mycobacterium tuberculosis display extensive cross-talk in vitro

Agrawal

Pandey

Rajankar

et al. 2015

Biochemical Journal

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Two-component systems (TCSs), which contain paired sensor kinase and response regulator proteins, form the primary apparatus for sensing and responding to environmental cues in bacteria. TCSs are thought to be highly specific, displaying minimal cross-talk, primarily due to the co-evolution of the participating proteins. To assess the level of cross-talk between the TCSs of Mycobacterium tuberculosis, we mapped the complete interactome of the M. tuberculosis TCSs using phosphotransfer profiling. Surprisingly, we found extensive cross-talk among the M. tuberculosis TCSs, significantly more than that in the TCSs in Escherichia coli or Caulobacter crescentus, thereby offering an alternate to specificity paradigm in TCS signalling. Nearly half of the interactions we detected were significant novel cross-interactions, unravelling a potentially complex signalling landscape. We classified the TCSs into specific 'one-to-one' and promiscuous 'one-to-many' and 'many-to-one' circuits. Using mathematical modelling, we deduced that the promiscuous signalling observed can explain several currently confounding observations about M. tuberculosis TCSs. Our findings suggest an alternative paradigm of bacterial signalling with significant cross-talk between TCSs yielding potentially complex signalling landscapes.

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Section: Mathematical Modellingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The two-component signalling networks of Mycobacterium tuberculosis display extensive cross-talk in vitro

Agrawal

Pandey

Rajankar

et al. 2015

Biochemical Journal

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“…Two component systems of Mycobacterium tuberculosis have recently emerged as promising drug targets in anti-tuberculosis chemotherapy (2, 3, 26, 27), with several TCS RRs implicated in key adaptive responses such as response to pH, envelope stress, phosphate limitation and hypoxia (5). However, the mechanistic details of TCS signalling, especially the role of SKs and their ligand binding domains in modulating responses to these conditions are yet to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…Mycobacterium tuberculosis (Mtb), the causative agent of a disease that is now the leading cause of death due to a single infectious agent, is estimated to have infected 10.4 million people worldwide in 2016 (1). Two component signalling systems (TCSs) play an important role in multiple stages of the Mtb lifestyle within the host including regulating viability, host cell invasion, intracellular survival, phago-lysosomal fusion, dormancy and cell division (2). Moreover, the complete absence of TCSs in mammals and their importance in Mtb physiology also makes them attractive targets for anti-tubercular therapy (3, 4).…”

Section: Introductionmentioning

confidence: 99%

The histidine kinase PdtaS is a cyclic di-GMP binding metabolic sensor that controls mycobacterial adaptation to nutrient deprivation

Hariharan

Thakur

Singh

et al. 2019

Preprint

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Cell signalling relies on second messengers to transduce signals from the sensory 16 apparatus to downstream components of the signalling pathway. In bacteria, one of the most 17 important and ubiquitous second messengers is the small molecule cyclic diguanosine 18 monophosphate (c-di-GMP). While the biosynthesis, degradation and regulatory pathways 19 controlled by c-di-GMP are well characterized, the mechanisms through which c-di-GMP 20 controls these processes is not completely understood. Here we present the first report of a c-21 di-GMP regulated sensor histidine kinase previously named PdtaS (Rv3220c), which binds to 22 c-di-GMP at sub-micromolar concentrations, subsequently perturbing signalling of the PdtaS-23 PdtaR (Rv1626) two component system. Aided by biochemical analysis, molecular docking 24 and structural modelling, we have characterized the binding site of c-di-GMP in the GAF 25 domain of PdtaS. We show that a pdtaS knockout in M. smegmatis is severely compromised in 26 growth on amino acid deficient media and exhibits global transcriptional dysregulation. 27Perturbation of the c-di-GMP-PdtaS-PdtaR axis results in a cascade of cellular changes 28 recorded by a multi-parametric systems approach of transcriptomics, unbiased metabolomics 29 and lipid analyses. 30One-sentence summary: The universal bacterial second messenger cyclic di-GMP controls 31 the mycobacterial nutrient stress response 32Among the less understood TCSs of Mtb is the highly conserved PdtaS-PdtaR TCS. Studies 48 have shown PdtaR to be essential for survival on medium containing cholesterol as the sole 49 carbon source (6) and intracellular growth during macrophage infection (7). Its cognate SK 50PdtaS has been implicated in controlling ribosomal protein composition and sensitivity to 51 ribosome targeting antibiotics, membrane transport inhibitors and respiratory chain antagonists 52in Mycobacterium smegmatis (8). However, neither the ligands that triggers the activation of 53 this TCS nor the adaptive responses that result from PdtaS-PdtaR signalling are known. 54In this study, we use a knockout of pdtaS in Mycobacterium smegmatis to identify the role of 55 this conserved TCS in mycobacterial physiology. Using comparative metabolomics and in 56 silico docking, we have identified c-di-GMP as a ligand for PdtaS. Furthermore, we show that 57PdtaS phosphorylation and integrity of the c-di-GMP binding site are essential for growth, lipid 58 homeostasis and transcriptional adaptation during nutrient deprivation. Finally, using protein-59 protein interaction network modelling of the transcriptomic data, we uncover a novel 60 interactome that connects diverse metabolic pathways in mycobacteria. 61 Results 62 PdtaS deficiency results in poor growth during nutrient deprivation 63In order to study the role of PdtaS and PdtaS-PdtaR signalling in the physiology of 64 mycobacteria, we deleted pdtaS (MSMEG_1918) in M. smegmatis using specialized 65 transduction as described previously (9) and verified the deletion using PCR and Southern blot 66...

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Cyclic di‐GMP sensing histidine kinase PdtaS controls mycobacterial adaptation to carbon sources

et al. 2021

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Cell signaling relies on second messengers to transduce signals from the sensory apparatus to downstream signaling pathway components. In bacteria, one of the most important and ubiquitous second messenger is the small molecule cyclic diguanosine monophosphate (c‐di‐GMP). While the biosynthesis, degradation, and regulatory pathways controlled by c‐di‐GMP are well characterized, the mechanisms through which c‐di‐GMP controls these processes are not entirely understood. Herein we present the report of a c‐di‐GMP sensing sensor histidine kinase PdtaS (Rv3220c), which binds to c‐di‐GMP at submicromolar concentrations, subsequently perturbing signaling of the PdtaS‐PdtaR (Rv1626) two‐component system. Aided by biochemical analysis, genetics, molecular docking, FRET microscopy, and structural modelling, we have characterized the binding of c‐di‐GMP in the GAF domain of PdtaS. We show that a pdtaS knockout in Mycobacterium smegmatis is severely compromised in growth on amino acid deficient media and exhibits global transcriptional dysregulation. The perturbation of the c‐di‐GMP‐PdtaS‐PdtaR axis results in a cascade of cellular changes recorded by a multiparametric systems’ approach of transcriptomics, unbiased metabolomics, and lipid analyses.

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Two-Component Signalling Systems of M. tuberculosis: Regulators of Pathogenicity and More

Cited by 5 publications

References 117 publications

The two-component signalling networks of Mycobacterium tuberculosis display extensive cross-talk in vitro

The two-component signalling networks of Mycobacterium tuberculosis display extensive cross-talk in vitro

The histidine kinase PdtaS is a cyclic di-GMP binding metabolic sensor that controls mycobacterial adaptation to nutrient deprivation

Cyclic di‐GMP sensing histidine kinase PdtaS controls mycobacterial adaptation to carbon sources

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