title: The M. tuberculosis HAD phosphatase (Rv3042c) interacts with host proteins and is inhibited by Clofazimine.
abstract: Mycobacterium tuberculosis codes for a HAD-phosphatase, Rv3042c (MtSerB2), that has earlier been characterized as a metabolic enzyme. Here we demonstrate that MtSerB2 is secreted into the cytosol of infected macrophages and is found in bronchoalveolar lavage samples of tuberculosis patients. MtSerB2 induces significant cytoskeleton rearrangements through cofilin activation and affects the expression of genes that regulate actin dynamics. It specifically interacts with HSP90, HSP70 and HSP27 that block apoptotic pathways and not with other HSPs. It actively dephosphorylates MAPK-p38 and NF-kappa B p65 that play crucial roles in inflammatory and immune responses. This in turn leads to down-regulation of Interleukin 8, a chemotactic and inflammatory cytokine. Finally, during evaluation of inhibitors against MtSerB2 we found that Clofazimine, a drug being evaluated for XDR and MDR tuberculosis, inhibits MtSerB2 phosphatase activity and reverses the above effects and interactions with host proteins. Overall, the study identifies that MtSerB2 has new functions that might help the pathogen to evade the host's immune response.
authors.affiliation: Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, Uttar Pradesh, India.
authors.forename: Sonal
authors.initials: S
authors.lastname: Shree
authors.affiliation: Biochemistry Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, Uttar Pradesh, India.
authors.forename: Abhishek Kumar
authors.initials: AK
authors.lastname: Singh
authors.affiliation: Microbiology Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, Uttar Pradesh, India.
authors.forename: Richa
authors.initials: R
authors.lastname: Saxena
authors.affiliation: Biochemistry Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, Uttar Pradesh, India.
authors.forename: Harish
authors.initials: H
authors.lastname: Kumar
authors.affiliation: Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, Uttar Pradesh, India.
authors.forename: Aparna
authors.initials: A
authors.lastname: Agarwal
authors.affiliation: Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, Uttar Pradesh, India.
authors.forename: Vijay Kumar
authors.initials: VK
authors.lastname: Sharma
authors.affiliation: Microbiology Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, Uttar Pradesh, India.
authors.forename: Kanchan
authors.initials: K
authors.lastname: Srivastava
authors.affiliation: Microbiology Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, Uttar Pradesh, India.
authors.forename: Kishore Kumar
authors.initials: KK
authors.lastname: Srivastava
authors.affiliation: Biochemistry Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, Uttar Pradesh, India.
authors.forename: Sabyasachi
authors.initials: S
authors.lastname: Sanyal
authors.affiliation: Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, Uttar Pradesh, India. r_ravishankar@cdri.res.in.
authors.forename: Ravishankar
authors.initials: R
authors.lastname: Ramachandran
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects; D000199:Actins / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002460:Cell Line; D019281:Dimerization; D015536:Down-Regulation / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism / Q000382:microbiology; D062105:Molecular Docking Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020836:Protein Structure, Quaternary; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000302:isolation & purification; D051996:Transcription Factor RelA / Q000378:metabolism; D014376:Tuberculosis / Q000175:diagnosis / Q000276:immunology / Q000382:microbiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000199:Actins; D001426:Bacterial Proteins; D006360:Heat-Shock Proteins; D016209:Interleukin-8; D011994:Recombinant Proteins; D051996:Transcription Factor RelA; D048051:p38 Mitogen-Activated Protein Kinases; D010744:Phosphoric Monoester Hydrolases
keywords: Actin dynamics; Clofazimine; Drug target; Immune evasion; MAPK p38; Mycobacterium tuberculosis; Phosphoserine phosphatase; Riminophenazine; Secretory protein