The Multifunctional PE_PGRS11 Protein from Mycobacterium tuberculosis Plays a Role in Regulating Resistance to Oxidative Stress
| Autor: | Saurabh Mishra, Namineni Sukumar, Shripad A. Patil, Nagasuma Chandra, Parthasarathi Ajitkumar, Beenu Joshi, Kithiganahalli Narayanaswamy Balaji, Rashmi Chaturvedi, Yeddula Narayana, Shambhuprasad Kotresh Togarsimalemath, Vishwa Mohan Katoch, Kushagra Bansal, Nisha Kapoor |
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| Rok vydání: | 2010 |
| Předmět: |
p38 mitogen-activated protein kinases
Mycobacterium smegmatis medicine.disease_cause p38 Mitogen-Activated Protein Kinases Biochemistry Phosphatidylinositol 3-Kinases Bacterial Proteins medicine Humans Tuberculosis Supercomputer Education & Research Centre Molecular Biology B cell Mitogen-Activated Protein Kinase 1 Phosphoglycerate Mutase Microbiology & Cell Biology Antigens Bacterial Mitogen-Activated Protein Kinase 3 biology Effector NF-kappa B Membrane Proteins Epithelial Cells Hydrogen Peroxide Mycobacterium tuberculosis Cell Biology Oxidants NFKB1 biology.organism_classification Toll-Like Receptor 2 Cell biology Pulmonary Alveoli Oxidative Stress TLR2 medicine.anatomical_structure Proto-Oncogene Proteins c-bcl-2 Cyclooxygenase 2 Additions and Corrections Signal transduction Oxidative stress Signal Transduction |
| Zdroj: | Journal of Biological Chemistry. 285:30389-30403 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m110.135251 |
| Popis: | 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-kappa B 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. |
| Databáze: | OpenAIRE |
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