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In silico evidence for extensive Ser/Thr phosphorylation of Mycobacterium tuberculosis two-component signalling systems
Mycobacterium tuberculosis has the innate ability to adapt and survive the intracellular environments during infection. Two-component signalling (TCS) systems and serine (Ser)/threonine (Thr) protein kinases facilitate metabolic and growth adaptation by directing transcriptomic reprogramming in response to environmental stimuli. Presently, little is known about the post-translational regulation of TCS proteins through O-phosphorylation. Using the NetPhosBac 1.0 in silico tool, we screened components of M. tuberculosis TCS systems for potential Ser/Thr phosphosites. We report extensive Ser/Thr phosphorylation of sensor kinases and response regulator proteins, suggesting that it might be a distinct mechanism enabling the co-regulation of pathways impacting adaptive changes in mycobacterial growth and metabolism
Keywords
Mycobacterium tuberculosis, post-transla-tional modification, serine/threonine protein kinase, two -component systems response regulators.
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- Adigun, R. and Singh, R., Tuberculosis. In StatPearls, StatPearls Publishing, Treasure Island, Florida, USA, 2021; https://www.ncbi. nlm.nih.gov/books/NBK441916/
- Cole, S. T. et al., Deciphering the biology of Mycobacterium tuber-culosis from the complete genome sequence. Nature, 1998, 393(6685), 537–544.
- Av-Gay, Y. and Everett, M., The eukaryotic-like Ser/Thr protein kinases of Mycobacterium tuberculosis. Trends Microbiol., 2000, 8, 238–244.
- Nixon, B. T., Ronson, C. W. and Ausubel, F. M., Two-component regulatory systems responsive to environmental stimuli share strongly conserved domains with the nitrogen assimilation regula-tory genes ntrB and ntrC. Proc. Natl. Acad. Sci. USA, 1986, 83, 7850–7854.
- Bretl, D. J., Demetriadou, C. and Zahrt, T. C., Adaptation to envi-ronmental stimuli within the host: two-component signal transduc-tion systems of Mycobacterium tuberculosis. Microbiol. Mol. Biol. Rev., 2011, 75, 566–582.
- Parish, T., Smith, D. A., Kendall, S., Casali, N., Bancroft, G. J. and Stoker, N. G., Deletion of two-component regulatory systems in-creases the virulence of Mycobacterium tuberculosis. Infect. Immu-nol., 2003, 71, 1134–1140.
- Zahrt, T. C. and Deretic, V., An essential two-component signal transduction system in Mycobacterium tuberculosis. J. Bacteriol., 2000, 182, 3832–3838.
- Haydel, S. E., Malhotra, V., Cornelison, G. L. and Clark-Curtiss, J. E., The prrAB two-component system is essential for Mycobacterium tuberculosis viability and is induced under nitrogen-limiting condi-tions. J. Bacteriol., 2012, 194, 354–361.
- Fernandez, P. et al., The Ser/Thr protein kinase PknB is essential for sus-taining mycobacterial growth. J. Bacteriol., 2006, 188, 7778–7784.
- Kang, C.-M., Abbott, D. W., Park, S. T., Dascher, C. C., Cantley, L. C. and Husson, R. N., The Mycobacterium tuberculosis serine/ threonine kinases PknA and PknB: substrate identification and reg-ulation of cell shape. Genes Dev., 2005, 19, 1692–1704.
- Gopalaswamy, R., Narayanan, S., Chen, B., Jacobs, W. R. and Av-Gay, Y., The serine/threonine protein kinase PknI controls the growth of Mycobacterium tuberculosis upon infection. FEMS Microbiol. Lett., 2009, 295, 23–29.
- Jang, J. et al., Functional characterization of the Mycobacterium tuberculosis serine/threonine kinase PknJ. Microbiology, 2021, 156, 1619–1631.
- Malhotra, V., Arteaga-Cortés, L. T., Clay, G. and Clark-Curtiss, J. E., Mycobacterium tuberculosis protein kinase K confers survival ad-vantage during early infection in mice and regulates growth in culture and during persistent infection: implications for immune modula-tion. Microbiology (Reading), 2010, 156, 2829–2841.
- Papavinasasundaram, K. G., Chan, B., Chung, J.-H., Colston, M. J., Davis, E. O. and Av-Gay, Y., Deletion of the Mycobacterium tu-berculosis pknH gene confers a higher bacillary load during the chronic phase of infection in BALB/c mice. J. Bacteriol., 2005, 187(16), 5751–5760.
- Agrawal, R., Sahoo, B. K. and Saini, D. K., Cross-talk and specificity in two-component signal transduction pathways. Future Microbiol., 2016, 11, 685–697.
- Agrawal, R., Pandey, A., Rajankar, M. P., Dixit, N. M. and Saini, D. K., The two-component signalling networks of Mycobacterium tuberculosis display extensive cross-talk in vitro. Biochem. J., 2015, 469, 121–134.
- Park, E.-J., Kwon, Y.-M., Lee, J.-W., Kang, H.-Y. and Oh, J.-I., Dual control of RegX3 transcriptional activity by SenX3 and PknB. J. Biol. Chem., 2019, 294, 11023–11034.
- Saini, D. K., Malhotra, V., Dey, D., Pant, N., Das, T. K. and Tyagi, J. S., DevR–DevS is a bona fide two-component system of Myco-bacterium tuberculosis that is hypoxia-responsive in the absence of the DNA-binding domain of DevR. Microbiology (Reading), 2004, 150, 865–875.
- Bae, H.-J. et al., Inhibition of the DevSR two-component system by overexpression of Mycobacterium tuberculosis PknB in Mycobac-terium smegmatis. Mol. Cells, 2017, 40, 632–642.
- Chao, J. D. et al., Convergence of Ser/Thr and two-component signal-ing to coordinate expression of the dormancy regulon in Mycobac-terium tuberculosis*[S]. J. Biol. Chem., 2010, 285, 29239–29246.
- Malhotra, V. et al., Mycobacterium tuberculosis PknK substrate profiling reveals essential transcription terminator protein rho and two-component response regulators PrrA and MtrA as novel targets for phosphorylation. Microbiol. Spectr., 2022, 10, e0135421.
- Mishra, A. K., Yabaji, S. M., Dubey, R. K., Dhamija, E. and Sriva-stava, K. K., Dual phosphorylation in response regulator protein PrrA is crucial for intracellular survival of mycobacteria consequent upon transcriptional activation. Biochem. J., 2017, 474, 4119–4136.
- Miller, M. L., Soufi, B., Jers, C., Blom, N., Macek, B. and Mijako-vic, I., NetPhosBac – a predictor for Ser/Thr phosphorylation sites in bacterial proteins. Proteomics, 2009, 9, 116–125.
- Frando, A. et al., The Mycobacterium tuberculosis protein O-pho-sphorylation landscape (preprint). Microbiology, 2022.
- Shrivastava, R., Das, D. R., Wiker, H. G. and Das, A. K., Functional insights from the molecular modelling of a novel two -component system. Biochem. Biophys. Res. Commun., 2006, 344, 1327–1333.
- Cowley, S. et al., The Mycobacterium tuberculosis protein serine/ threonine kinase PknG is linked to cellular glutamate/glutamine levels and is important for growth in vivo. Mol. Microbiol., 2004, 52, 1691–1702.
- Kumar, P. et al., The Mycobacterium tuberculosis protein kinase K modulates activation of transcription from the promoter of myco-bacterial monooxygenase operon through phosphorylation of the transcriptional regulator VirS. J. Biol. Chem., 2009, 284, 11090– 11099.
- Gautam, U. S. et al., Mycobacterium tuberculosis sensor kinase DosS modulates the autophagosome in a DosR-independent man-ner. Commun. Biol., 2019, 2, 349.
- Kundu, M., The role of two-component systems in the physiology of Mycobacterium tuberculosis. IUBMB Life, 2018, 70, 710–717.
- Li, X. et al., Role of two-component regulatory systems in intracel-lular survival of Mycobacterium tuberculosis. J. Cell. Biochem., 2019, 120, 12197–12207.
- Malhotra, V., Agrawal, R., Duncan, T. R., Saini, Deepak, K. and Clark-Curtiss, J. E., Mycobacterium tuberculosis response regulators, DevR and NarL, interact in vivo and co-regulate gene expression during aerobic nitrate metabolism. J. Biol. Chem., 2015, 290, 8294– 8309.
- Jang, J. et al., Functional characterization of the Mycobacterium tuberculosis serine/threonine kinase PknJ. Microbiology (Reading), 2010, 156, 1619–1631.
- Chakraborti, P. K., Matange, N., Nandicoori, V. K., Singh, Y., Tyagi, J. S. and Visweswariah, S. S., Signalling mechanisms in Mycobacteria. Tuberculosis, 2011, 91, 432–440.
- Bhattacharya, M., Biswas, A. and Das, A. K., Interaction analysis of TcrX/Y two component system from Mycobacterium tuberculo-sis. Biochimie, 2010, 92, 263–272.
- Hatzios, S. K. et al., Osmosensory signaling in Mycobacterium tu-berculosis mediated by a eukaryotic-like Ser/Thr protein kinase. Proc. Natl. Acad. Sci. USA, 2013, 110, E5069–E5077.
- Hariharan, V. N. et al., Cyclic di-GMP sensing histidine kinase PdtaS controls mycobacterial adaptation to carbon sources. FASEB J., 2021, 35, e21475.
- Xu, Y., You, D. and Ye, B.-C., RegX3 controls glyoxylate shunt and Mycobacteria survival by directly regulating the transcription of isocitrate lyase gene in Mycobacterium smegmatis. ACS Infect. Dis., 2021, 7, 927–936.
- Singh, K. K. et al., Acetylation of response regulator proteins, TcrX and MtrA in M. tuberculosis tunes their phosphotransfer abi -lity and modulates two-component signaling crosstalk. J. Mol. Biol., 2019, 431, 777–793.
- Lee, H.-N., Jung, K.-E., Ko, I.-J., Baik, H. S. and Oh, J.-I., Protein– protein interactions between histidine kinases and response regula-tors of Mycobacterium tuberculosis H37Rv. J. Microbiol., 2012, 50, 270–277.
- Vashist, A., Malhotra, V., Sharma, G., Tyagi, J. S. and Clark-Curtiss, J. E., Interplay of PhoP and DevR response regulators defines ex-pression of the dormancy regulon in virulent Mycobacterium tuber-culosis. J. Biol. Chem., 2018, 293, 16413–16425.
- Szklarczyk, D. et al., STRING v10: protein–protein interaction networks, integrated over the tree of life. Nucleic Acids Res., 2015, 43, D447–D452
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