title: EspR-dependent ESAT-6 Protein Secretion of Mycobacterium tuberculosis Requires the Presence of Virulence Regulator PhoP.
abstract: Attenuation of Mycobacterium bovis BCG strain is related to the loss of the RD1-encoded ESX-1 secretion system. The ESX-1 system secretes virulence factor ESAT-6 that plays a critical role in modulation of the host immune system, which is essential for establishment of a productive infection. Previous studies suggest that among the reasons for attenuation of Mycobacterium tuberculosis H37Ra is a mutation in the phoP gene that interferes with the ESX-1 secretion system and inhibits secretion of ESAT-6. Here, we identify a totally different and distinct regulatory mechanism involving PhoP and transcription regulator EspR on transcriptional control of the espACD operon, which is required for ESX-1-dependent ESAT-6 secretion. Although both of these regulators are capable of influencing espACD expression, we show that activation of espACD requires direct recruitment of both PhoP and EspR at the espACD promoter. The most fundamental insights are derived from the inhibition of EspR binding at the espACD regulatory region of the phoP mutant strain because of PhoP-EspR protein-protein interactions. Based on these results, a model is proposed suggesting how PhoP and EspR protein-protein interactions contribute to activation of espACD expression and, in turn, control ESAT-6 secretion, an essential pathogenic determinant of M. tuberculosis Together, these results have significant implications on the mechanism of virulence regulation of M. tuberculosis.
authors.affiliation: From the Council of Scientific and Industrial Research-Institute of Microbial Technology, Sector 39 A, Chandigarh 160036, India.
authors.forename: Vijjamarri
authors.initials: V
authors.lastname: Anil Kumar
authors.affiliation: From the Council of Scientific and Industrial Research-Institute of Microbial Technology, Sector 39 A, Chandigarh 160036, India.
authors.forename: Rajni
authors.initials: R
authors.lastname: Goyal
authors.affiliation: From the Council of Scientific and Industrial Research-Institute of Microbial Technology, Sector 39 A, Chandigarh 160036, India.
authors.forename: Roohi
authors.initials: R
authors.lastname: Bansal
authors.affiliation: From the Council of Scientific and Industrial Research-Institute of Microbial Technology, Sector 39 A, Chandigarh 160036, India.
authors.forename: Nisha
authors.initials: N
authors.lastname: Singh
authors.affiliation: From the Council of Scientific and Industrial Research-Institute of Microbial Technology, Sector 39 A, Chandigarh 160036, India.
authors.forename: Ritesh Rajesh
authors.initials: RR
authors.lastname: Sevalkar
authors.affiliation: From the Council of Scientific and Industrial Research-Institute of Microbial Technology, Sector 39 A, Chandigarh 160036, India.
authors.forename: Ashwani
authors.initials: A
authors.lastname: Kumar
authors.affiliation: From the Council of Scientific and Industrial Research-Institute of Microbial Technology, Sector 39 A, Chandigarh 160036, India dibyendu@imtech.res.in.
authors.forename: Dibyendu
authors.initials: D
authors.lastname: Sarkar
mesh_terms: D000942:Antigens, Bacterial / Q000235:genetics; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D058947:Bacterial Secretion Systems / Q000235:genetics / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial / Q000502:physiology*; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D009876:Operon / Q000502:physiology; D020218:Response Elements / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D037521:Virulence Factors / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D058947:Bacterial Secretion Systems; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D014157:Transcription Factors; D037521:Virulence Factors; C061064:PhoP protein, Bacteria
keywords: DNA-protein interaction; Mycobacterium tuberculosis; gene regulation; microbial pathogenesis; protein secretion