title: M. tuberculosis Secretory Protein ESAT-6 Induces Metabolic Flux Perturbations to Drive Foamy Macrophage Differentiation.
abstract: The Foamy Macrophage (FM) differentiation forms a major component of the host dependent survival axis of M. tuberculosis. The FM which are characterized by the intracellular accumulation of lipid bodies (LBs), ensure a privileged existence for the bacilli through ready provision of nutrients and by conferring protection against bactericidal pathways. The mycobacterial secretory protein ESAT-6 has been identified as the molecular mediator of the FM differentiation process although little is known about the mechanism through which it induces this process. In the present study, we show that ESAT-6 induces GLUT-1 mediated enhanced glucose uptake by macrophages which is coupled to metabolic flux perturbations in the glycolytic pathway caused by differential rates of reaction at several steps in the pathway. Two major changes identified were the simultaneous buildup of DHAP (for Triglyceride synthesis) and AcCoA (for synthesis of 3-HB, ligand for the anti-lipolytic GPR109A). We also show that part of the observed effects involve protein- protein interactions between ESAT-6 and the macrophage glycolytic enzymes, Enolase1 and Phosphoglycerate kinase1.
authors.affiliation: Drug Discovery Research Centre, Translational Health Science &Technology Institute NCR Biotech Science Cluster, 3rd Milestone, Faridabad - Gurgaon Expressway, Faridabad - 121001, India.
authors.forename: Varshneya
authors.initials: V
authors.lastname: Singh
authors.affiliation: Department of Biochemistry, University of Delhi South Campus, New Delhi, 110021, India.
authors.forename: Charanpreet
authors.initials: C
authors.lastname: Kaur
authors.affiliation: Department of Biochemistry, University of Delhi South Campus, New Delhi, 110021, India.
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Chaudhary
authors.affiliation: Immunology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, 110067, India.
authors.forename: Kanury V S
authors.initials: KV
authors.lastname: Rao
authors.affiliation: Drug Discovery Research Centre, Translational Health Science &Technology Institute NCR Biotech Science Cluster, 3rd Milestone, Faridabad - Gurgaon Expressway, Faridabad - 121001, India.
authors.forename: Samrat
authors.initials: S
authors.lastname: Chatterjee
mesh_terms: D000942:Antigens, Bacterial / Q000378:metabolism; D001426:Bacterial Proteins / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D005487:Foam Cells / Q000378:metabolism* / Q000502:physiology*; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D009169:Mycobacterium tuberculosis / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs / Q000502:physiology; D014376:Tuberculosis / Q000378:metabolism / Q000382:microbiology
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D051272:Glucose Transporter Type 1