The Multifunctional PE_PGRS11 Protein from Mycobacterium tuberculosis Plays a Role in Regulating Resistance to Oxidative Stress

• Published in: The Journal of biological chemistry 2010-10, Vol.285 (40), p.30389-30403
• Main Authors: Chaturvedi, Rashmi, Bansal, Kushagra, Narayana, Yeddula, Kapoor, Nisha, Sukumar, Namineni, Togarsimalemath, Shambhuprasad Kotresh, Chandra, Nagasuma, Mishra, Saurabh, Ajitkumar, Parthasarathi, Joshi, Beenu, Katoch, Vishwa Mohan, Patil, Shripad A., Balaji, Kithiganahalli N.
• Format: Article
• Language: English
• Subjects: Adenovirus; Antigens, Bacterial - genetics; Antigens, Bacterial - immunology; Antigens, Bacterial - metabolism; Bacterial Proteins - genetics; Bacterial Proteins - immunology; Bacterial Proteins - metabolism; Cyclooxygenase (COX) Pathway; Cyclooxygenase 2 - biosynthesis; Epithelial Cells - metabolism; Epithelial Cells - microbiology; Humans; Hydrogen Peroxide - pharmacology; Membrane Proteins - genetics; Membrane Proteins - immunology; Membrane Proteins - metabolism; Microbiology; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - genetics; Mitogen-Activated Protein Kinase 3 - metabolism; Molecular Bases of Disease; Multifunctional Protein; Mycobacterium smegmatis; Mycobacterium smegmatis - enzymology; Mycobacterium smegmatis - genetics; Mycobacterium smegmatis - immunology; Mycobacterium tuberculosis; Mycobacterium tuberculosis - enzymology; Mycobacterium tuberculosis - genetics; Mycobacterium tuberculosis - immunology; NF-kappa B - genetics; NF-kappa B - metabolism; Oxidants - pharmacology; Oxidative Stress; p38 MAPK; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - immunology; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Phosphoglycerate Mutase - genetics; Phosphoglycerate Mutase - immunology; Phosphoglycerate Mutase - metabolism; PI 3-Kinase; Proto-Oncogene Proteins c-bcl-2 - biosynthesis; Pulmonary Alveoli - metabolism; Pulmonary Alveoli - microbiology; Signal Transduction - immunology; Toll-Like Receptor 2 - metabolism; Toll-like Receptors (TLR); Tuberculosis - enzymology; Tuberculosis - genetics; Tuberculosis - immunology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.135251

Mycobacterium tuberculosis utilizes unique strategies to survive amid the hostile environment of infected host cells. Infection-specific expression of a unique mycobacterial cell surface antigen that could modulate key signaling cascades can act as a key survival strategy in curtailing host effector responses like oxidative stress. We demonstrate here that hypothetical PE_PGRS11 ORF encodes a functional phosphoglycerate mutase. The transcriptional analysis revealed that PE_PGRS11 is a hypoxia-responsive gene, and enforced expression of PE_PGRS11 by recombinant adenovirus or Mycobacterium smegmatis imparted resistance to alveolar epithelial cells against oxidative stress. PE_PGRS11-induced resistance to oxidative stress necessitated the modulation of genetic signatures like induced expression of Bcl2 or COX-2. This modulation of specific antiapoptotic molecular signatures involved recognition of PE_PGRS11 by TLR2 and subsequent activation of the PI3K-ERK1/2-NF-κB signaling axis. Furthermore, PE_PGRS11 markedly diminished H2O2-induced p38 MAPK activation. Interestingly, PE_PGRS11 protein was exposed at the mycobacterial cell surface and was involved in survival of mycobacteria under oxidative stress. Furthermore, PE_PGRS11 displayed differential B cell responses during tuberculosis infection. Taken together, our investigation identified PE_PGRS11 as an in vivo expressed immunodominant antigen that plays a crucial role in modulating cellular life span restrictions imposed during oxidative stress by triggering TLR2-dependent expression of COX-2 and Bcl2. These observations clearly provide a mechanistic basis for the rescue of pathogenic Mycobacterium-infected lung epithelial cells from oxidative stress.