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Convergence of two global regulators to coordinate expression of essential virulence determinants of Mycobacterium tuberculosis

Cyclic AMP (cAMP) is known to function as a global regulator of Mycobacterium tuberculosis gene expression. Sequence-based transcriptomic profiling identified the mycobacterial regulon controlled by the cAMP receptor protein, CRP. In this study, we identified a new subset of CRP-associated genes inc...

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Autores principales: Khan, Hina, Paul, Partha, Sevalkar, Ritesh Rajesh, Kachhap, Sangita, Singh, Balvinder, Sarkar, Dibyendu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9645806/
https://www.ncbi.nlm.nih.gov/pubmed/36350294
http://dx.doi.org/10.7554/eLife.80965
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author Khan, Hina
Paul, Partha
Sevalkar, Ritesh Rajesh
Kachhap, Sangita
Singh, Balvinder
Sarkar, Dibyendu
author_facet Khan, Hina
Paul, Partha
Sevalkar, Ritesh Rajesh
Kachhap, Sangita
Singh, Balvinder
Sarkar, Dibyendu
author_sort Khan, Hina
collection PubMed
description Cyclic AMP (cAMP) is known to function as a global regulator of Mycobacterium tuberculosis gene expression. Sequence-based transcriptomic profiling identified the mycobacterial regulon controlled by the cAMP receptor protein, CRP. In this study, we identified a new subset of CRP-associated genes including virulence determinants which are also under the control of a major regulator, PhoP. Our results suggest that PhoP as a DNA binding transcription factor, impacts expression of these genes, and phosphorylated PhoP promotes CRP recruitment at the target promoters. Further, we uncover a distinct regulatory mechanism showing that activation of these genes requires direct recruitment of both PhoP and CRP at their target promoters. The most fundamental biological insight is derived from the inhibition of CRP binding at the regulatory regions in a PhoP-deleted strain owing to CRP-PhoP protein-protein interactions. Based on these results, a model is proposed suggesting how CRP and PhoP function as co-activators of the essential pathogenic determinants. Taken together, these results uncover a novel mode of regulation where a complex of two interacting virulence factors impact expression of virulence determinants. These results have significant implications on TB pathogenesis.
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spelling pubmed-96458062022-11-15 Convergence of two global regulators to coordinate expression of essential virulence determinants of Mycobacterium tuberculosis Khan, Hina Paul, Partha Sevalkar, Ritesh Rajesh Kachhap, Sangita Singh, Balvinder Sarkar, Dibyendu eLife Microbiology and Infectious Disease Cyclic AMP (cAMP) is known to function as a global regulator of Mycobacterium tuberculosis gene expression. Sequence-based transcriptomic profiling identified the mycobacterial regulon controlled by the cAMP receptor protein, CRP. In this study, we identified a new subset of CRP-associated genes including virulence determinants which are also under the control of a major regulator, PhoP. Our results suggest that PhoP as a DNA binding transcription factor, impacts expression of these genes, and phosphorylated PhoP promotes CRP recruitment at the target promoters. Further, we uncover a distinct regulatory mechanism showing that activation of these genes requires direct recruitment of both PhoP and CRP at their target promoters. The most fundamental biological insight is derived from the inhibition of CRP binding at the regulatory regions in a PhoP-deleted strain owing to CRP-PhoP protein-protein interactions. Based on these results, a model is proposed suggesting how CRP and PhoP function as co-activators of the essential pathogenic determinants. Taken together, these results uncover a novel mode of regulation where a complex of two interacting virulence factors impact expression of virulence determinants. These results have significant implications on TB pathogenesis. eLife Sciences Publications, Ltd 2022-11-09 /pmc/articles/PMC9645806/ /pubmed/36350294 http://dx.doi.org/10.7554/eLife.80965 Text en © 2022, Khan et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Microbiology and Infectious Disease
Khan, Hina
Paul, Partha
Sevalkar, Ritesh Rajesh
Kachhap, Sangita
Singh, Balvinder
Sarkar, Dibyendu
Convergence of two global regulators to coordinate expression of essential virulence determinants of Mycobacterium tuberculosis
title Convergence of two global regulators to coordinate expression of essential virulence determinants of Mycobacterium tuberculosis
title_full Convergence of two global regulators to coordinate expression of essential virulence determinants of Mycobacterium tuberculosis
title_fullStr Convergence of two global regulators to coordinate expression of essential virulence determinants of Mycobacterium tuberculosis
title_full_unstemmed Convergence of two global regulators to coordinate expression of essential virulence determinants of Mycobacterium tuberculosis
title_short Convergence of two global regulators to coordinate expression of essential virulence determinants of Mycobacterium tuberculosis
title_sort convergence of two global regulators to coordinate expression of essential virulence determinants of mycobacterium tuberculosis
topic Microbiology and Infectious Disease
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9645806/
https://www.ncbi.nlm.nih.gov/pubmed/36350294
http://dx.doi.org/10.7554/eLife.80965
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