title: Mycobacterium tuberculosis virulence-regulator PhoP interacts with alternative sigma factor SigE during acid-stress response.
abstract: The ability to sense acid stress and mount an appropriate adaptive response by Mycobacterium tuberculosis, which adapts a long-term residence in the macrophage phagosome, remains one of the critical features that defines mycobacterial physiology and its intracellular location. To understand the mechanistic basis of adaptation of the intracellular pathogen, we studied global regulation of M. tuberculosis gene expression in response to acid stress. Although recent studies indicate a role for the virulence-associated phoP locus in pH-driven adaptation, in this study, we discovered a strikingly novel regulatory mechanism, which controls acid-stress homeostasis. Using mycobacterial protein fragment complementation and in vitro interaction analyses, we demonstrate that PhoP interacts with acid-inducible extracytoplasmic SigE (one of the 13 M. tuberculosis sigma factors) to regulate a complex transcriptional program. Based on these results, we propose a model to suggest that PhoP-SigE interaction represents a major requirement for the global acid stress response, absence of which leads to strongly reduced survival of the bacilli under acidic pH conditions. These results account for the significant growth attenuation of the phoP mutant in both cellular and animal models, and unravel the underlying global mechanism of how PhoP induces an adaptive program in response to acid stress.
authors.affiliation: CSIR-Institute of Microbial Technology, Sector 39 A, Chandigarh, 160036, India.
authors.forename: Roohi
authors.initials: R
authors.lastname: Bansal
authors.affiliation: CSIR-Institute of Microbial Technology, Sector 39 A, Chandigarh, 160036, India.
authors.forename: Vijjamarri
authors.initials: V
authors.lastname: Anil Kumar
authors.affiliation: CSIR-Institute of Microbial Technology, Sector 39 A, Chandigarh, 160036, India.
authors.forename: Ritesh Rajesh
authors.initials: RR
authors.lastname: Sevalkar
authors.affiliation: CSIR-Institute of Microbial Technology, Sector 39 A, Chandigarh, 160036, India.
authors.forename: Prabhat Ranjan
authors.initials: PR
authors.lastname: Singh
authors.affiliation: CSIR-Institute of Microbial Technology, Sector 39 A, Chandigarh, 160036, India.
authors.forename: Dibyendu
authors.identifier: http://orcid.org/0000-0001-6499-177X
authors.initials: D
authors.lastname: Sarkar
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial; D006863:Hydrogen-Ion Concentration; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000378:metabolism / Q000472:pathogenicity*; D019301:Oleic Acid / Q000494:pharmacology; D012808:Sigma Factor / Q000235:genetics* / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D012808:Sigma Factor; C111259:sigE protein, Bacteria; C061064:PhoP protein, Bacteria; D019301:Oleic Acid