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.
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.
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结核分枝杆菌6-kDa早期分泌的抗原靶靶（ESAT-6）蛋白通过调节细胞外信号调节激酶1/2的脂肪多糖下调脂多糖诱导的C-MYC表达。
DOI：
10.1186/1471-2172-8-24
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发表时间：
2007-10-03
期刊：
影响因子：
3
通讯作者：
Sharma, Pawan
中科院分区：
文献类型：
--
作者：
Ganguly, Niladri;Giang, Pham H.;Basu, Sandip K.;Mir, Fayaz Ahmad;Siddiqui, Imran;Sharma, Pawan
结核分枝杆菌 (Mtb) 每年导致 2-300 万人死亡。巨噬细胞内致病性分枝杆菌的持久存在是通过调节宿主细胞信号传导而实现的，这使得它们与其他非致病性物种不同，能够在宿主体内生存。近年来，结核分枝杆菌的分泌蛋白作为候选疫苗和诊断工具引起了人们的关注。它们以免疫系统为目标并引发假定的保护性反应；然而，它们也可能与该疾病的临床症状有关。我们的研究表明，RD-1 编码的分泌蛋白 ESAT-6 参与巨噬细胞内丝裂原激活蛋白 (MAP) 激酶信号通路的调节。 ESAT-6 在细胞质中诱导细胞外信号调节激酶 1/2 (ERK1/2) 磷酸化，但在细胞核中则不然，而 MAP 激酶通常会出现这种情况。 ESAT-6 还拮抗 LPS 诱导的细胞核中 ERK1/2 磷酸化。 ESAT-6 与原钒酸钠（酪氨酸磷酸酶抑制剂）一起刺激细胞可恢复细胞核中 ERK1/2 的磷酸化，表明细胞核中某些假定的磷酸酶对 ERK1/2 进行主动去磷酸化。此外，发现 ESAT-6 以 ERK1/2 依赖性方式下调 LPS 诱导基因 c-myc 的表达。本研究表明结核分枝杆菌分泌蛋白在调节巨噬细胞信号通路特别是 ERK1/2 MAP 激酶通路中的作用。这种调节似乎是通过限制细胞核中 ERK1/2 的激活来实现的，最终影响巨噬细胞基因的表达。这可能是结核分枝杆菌分泌蛋白调节巨噬细胞内基因表达的机制。
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.
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影响因子：
56.9
作者：
Johnson, GL;Lapadat, R
通讯作者：
Lapadat, R
影响因子：
11.4
作者：
Brunet, A;Roux, D;Pouysségur, J
通讯作者：
Pouysségur, J
DOI：
10.1073/pnas.0504922102
发表时间：
2005-07-26
影响因子：
11.1
作者：
Fortune, SM;Jaeger, A;Rubin, EJ
通讯作者：
Rubin, EJ
影响因子：
3.6
作者：
Gao, LY;Guo, S;Brown, EJ
通讯作者：
Brown, EJ
影响因子：
3.6
作者：
Guinn, KM;Hickey, MJ;Sherman, DR
通讯作者：
Sherman, DR