Functioning of Mycobacterial Heat Shock Repressors Requires the Master Virulence Regulator PhoP

A hallmark feature of pathogenesis lies in the ability of the pathogen to survive within macrophages under a stressful environment. Thus, coordinated regulation of stress proteins is critically important for an effective adaptive response of , the failure of which results in elevated immune recognit...

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Bibliographic Details
Published in:Journal of bacteriology 2019-06, Vol.201 (12)
Main Authors: Sevalkar, Ritesh Rajesh, Arora, Divya, Singh, Prabhat Ranjan, Singh, Ranjeet, Nandicoori, Vinay K, Karthikeyan, Subramanian, Sarkar, Dibyendu
Format: Article
Language:English
Subjects:
Bacilli
Bacterial Proteins - genetics
Bacteriology
Control
Deoxyribonucleic acid
DNA
Gene expression
Gene Expression Regulation, Bacterial
Heat shock proteins
Heat-Shock Proteins - genetics
Humans
Infections
Macrophages
Macrophages - microbiology
Mycobacterium tuberculosis - genetics
Mycobacterium tuberculosis - pathogenicity
Pathogenesis
Promoter Regions, Genetic
Protein interaction
Regulators
Repressor Proteins - genetics
Repressors
Stress
Stress proteins
Transcription factors
Transcription Factors - genetics
Tuberculosis
Virulence
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Summary:A hallmark feature of pathogenesis lies in the ability of the pathogen to survive within macrophages under a stressful environment. Thus, coordinated regulation of stress proteins is critically important for an effective adaptive response of , the failure of which results in elevated immune recognition of the tubercle bacilli with reduced survival during chronic infections. Here, we show that virulence regulator PhoP impacts the global regulation of heat shock proteins, which protect against stress generated by macrophages during infection. Our results identify that in addition to classical DNA-protein interactions, newly discovered protein-protein interactions control complex mechanisms of expression of heat shock proteins, an essential pathogenic determinant of While the C-terminal domain of PhoP binds to its target promoters, the N-terminal domain of the regulator interacts with the C-terminal end of the heat shock repressors. Remarkably, our findings delineate a regulatory pathway which involves three major transcription factors, PhoP, HspR, and HrcA, that control recruitment of the regulators within the target genes and regulate stress-specific expression of heat shock proteins via protein-protein interactions. The results have implications on the mechanism of regulation of PhoP-dependent stress response in The regulation of heat shock proteins which protect against stress generated by macrophages during infection is poorly understood. In this study, we show that PhoP, a virulence regulator of the tubercle bacilli, controls heat shock-responsive genes, an essential pathogenic determinant of Our results unravel that in addition to classical DNA-protein interactions, complex mechanisms of regulation of heat shock-responsive genes occur through multiple protein-protein interactions. Together, these findings delineate a fundamental regulatory pathway where transcription factors PhoP, HspR, and HrcA interact with each other to control stress-specific expression of heat shock proteins.
ISSN:0021-9193
1098-5530
DOI:10.1128/JB.00013-19