title: The multifunctional PE_PGRS11 protein from Mycobacterium tuberculosis plays a role in regulating resistance to oxidative stress.
abstract: 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 H(2)O(2)-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.
authors.affiliation: Department of Microbiology and Cell Biology, Supercomputer Education and Research Centre, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Chaturvedi
authors.forename: Kushagra
authors.initials: K
authors.lastname: Bansal
authors.forename: Yeddula
authors.initials: Y
authors.lastname: Narayana
authors.forename: Nisha
authors.initials: N
authors.lastname: Kapoor
authors.forename: Namineni
authors.initials: N
authors.lastname: Sukumar
authors.forename: Shambhuprasad Kotresh
authors.initials: SK
authors.lastname: Togarsimalemath
authors.forename: Nagasuma
authors.initials: N
authors.lastname: Chandra
authors.forename: Saurabh
authors.initials: S
authors.lastname: Mishra
authors.forename: Parthasarathi
authors.initials: P
authors.lastname: Ajitkumar
authors.forename: Beenu
authors.initials: B
authors.lastname: Joshi
authors.forename: Vishwa Mohan
authors.initials: VM
authors.lastname: Katoch
authors.forename: Shripad A
authors.initials: SA
authors.lastname: Patil
authors.forename: Kithiganahalli N
authors.initials: KN
authors.lastname: Balaji
mesh_terms: D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D004847:Epithelial Cells / Q000378:metabolism* / Q000382:microbiology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D020102:Mycobacterium smegmatis / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010736:Phosphoglycerate Mutase / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011650:Pulmonary Alveoli / Q000378:metabolism* / Q000382:microbiology; D015398:Signal Transduction / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D014376:Tuberculosis / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D008565:Membrane Proteins; D016328:NF-kappa B; D016877:Oxidants; C440642:PE-PGRS protein, Mycobacterium; D019253:Proto-Oncogene Proteins c-bcl-2; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D006861:Hydrogen Peroxide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D019869:Phosphatidylinositol 3-Kinases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D010736:Phosphoglycerate Mutase