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

Niladri Ganguly, Pham H. Giang, Sandip K. Basu, Fayaz Mir, Imran Siddiqui, Pawan Sharma

Research output: Contribution to journalArticle

Abstract

Background: 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. Results: 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. Conclusion: 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.

Original languageEnglish
Article number24
JournalBMC Immunology
Volume8
DOIs
Publication statusPublished - Oct 3 2007

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Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Mycobacterium tuberculosis
Lipopolysaccharides
Down-Regulation
Macrophages
Mitogen-Activated Protein Kinases
Proteins
Phosphorylation
Phosphoric Monoester Hydrolases
Gene Expression
myc Genes
Vanadates
Mycobacterium
Tyrosine
Cause of Death
Immune System
Cytoplasm
Vaccines
Sodium

ASJC Scopus subject areas

  • Medicine(all)

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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. / Ganguly, Niladri; Giang, Pham H.; Basu, Sandip K.; Mir, Fayaz; Siddiqui, Imran; Sharma, Pawan.

In: BMC Immunology, Vol. 8, 24, 03.10.2007.

Research output: Contribution to journalArticle

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abstract = "Background: 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. Results: 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. Conclusion: 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.",
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