Mycobacterium tuberculosis 6-kDa early secreted antigenic target (ESAT-6) protein downregulates lipopolysaccharide induced c-myc expression by modulating the extracellular signal regulated kinases 1/2

• Published in: BMC immunology Vol. 8; no. 1; p. 24
• Main Authors: Ganguly, Niladri, Giang, Pham H, Basu, Sandip K, Mir, Fayaz Ahmad, Siddiqui, Imran, Sharma, Pawan
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 03.10.2007; BioMed Central; BMC
• Subjects: Animals; Antigens, Bacterial - metabolism; Bacterial Proteins - metabolism; Bacterial toxins; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cell Line; Development and progression; Down-Regulation; Extracellular Signal-Regulated MAP Kinases - metabolism; Gene Expression - drug effects; Health aspects; Immediate-Early Proteins; Lipopolysaccharides - immunology; Macrophages; Macrophages - drug effects; Macrophages - immunology; Macrophages - secretion; Mice; Mitogen-Activated Protein Kinases - metabolism; Mycobacterium tuberculosis; Mycobacterium tuberculosis - immunology; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation - drug effects; Protein Tyrosine Phosphatases - antagonists & inhibitors; Protein Tyrosine Phosphatases - metabolism; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins c-myc - metabolism; Recombinant Fusion Proteins - metabolism; Signal Transduction; Tuberculosis; Germany; India
• ISSN: 1471-2172; 1471-2172
• DOI: 10.1186/1471-2172-8-24

Mycobacterium tuberculosis (Mtb) causes death of 2-3 million people every year. The persistence of the pathogenic mycobacteria inside the macrophage occurs through modulation of host cell signaling which allows them, unlike the other non-pathogenic species, to survive inside the host. The secretory proteins of M. tuberculosis have gained attention in recent years both as vaccine candidates and diagnostic tools; they target the immune system and trigger a putatively protective response; however, they may also be involved in the clinical symptoms of the disease. Our studies showed that RD-1-encoded secretory protein ESAT-6 is involved in modulation of the mitogen-activated protein (MAP) kinase-signaling pathway inside the macrophage. ESAT-6 induced phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) in the cytoplasm but not in the nucleus, which normally is the case for MAP kinases. ESAT-6 also antagonized LPS-induced ERK1/2 phosphorylation in the nucleus. Stimulation of cells by ESAT-6 along with sodium orthovanadate (a tyrosine phosphatase inhibitor) restored phosphorylation of ERK1/2 in the nucleus, suggesting active dephosphorylation of ERK1/2 by some putative phosphatase(s) in the nucleus. Further, ESAT-6 was found to down regulate the expression of LPS-inducible gene c-myc in an ERK1/2-dependent manner. This study showed the effect of secretory proteins of M. tuberculosis in the modulation of macrophage signaling pathways particularly ERK1/2 MAP kinase pathway. This modulation appears to be achieved by limiting the ERK1/2 activation in the nucleus which ultimately affects the macrophage gene expression. This could be a mechanism by which secretory proteins of Mtb might modulate gene expression inside the macrophages.