Bim is a crucial regulator of apoptosis induced by Mycobacterium tuberculosis.
Bim is a crucial regulator of apoptosis induced by Mycobacterium tuberculosis.
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DOI：
10.1038/cddis.2014.313
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发表时间：
2014-07-17
影响因子：
9
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中科院分区：
文献类型：
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结核分枝杆菌是结核病的病原体，在体外和体内诱导受感染巨噬细胞凋亡。然而，控制这一过程的分子机制尚不清楚。为了研究线粒体凋亡途径在结核分枝杆菌诱导的细胞凋亡中的作用，我们分析了来自不同敲除小鼠的结核分枝杆菌感染的胚胎成纤维细胞（MEF）中的细胞死亡，以寻找参与该途径的基因。我们发现，在缺乏 Bak 和 Bax、半胱天冬酶 9 或刽子手半胱天冬酶 3 和 7 的情况下，结核分枝杆菌诱导的细胞凋亡被消除。值得注意的是，我们发现，缺乏 BH3 的 BCL-2 相互作用细胞死亡介体 (Bim) 蛋白的 MEF 也能抵抗这一过程。这些结果的相关性已在小鼠巨噬细胞系 J774 中得到证实，其中用靶向 Bim 的 siRNA 转染细胞会损害由有毒分枝杆菌诱导的细胞凋亡。值得注意的是，只有强毒菌株的感染，而不是 ESX-1 缺陷型减毒菌株（例如卡介苗和减毒结核分枝杆菌疫苗菌株 MTBVAC）的感染，才会诱导 Bim 上调和细胞凋亡，这可能表明毒力因子在此过程中早期分泌抗原靶点 6-kDa 蛋白。我们的结果表明 Bim 上调和细胞凋亡是由 p38MAPK 依赖性途径介导的。我们的研究结果表明，Bim 是结核分枝杆菌诱导的细胞凋亡的主要调节因子。
Mycobacterium tuberculosis, the causative agent of tuberculosis, induces apoptosis in infected macrophages in vitro and in vivo. However, the molecular mechanism controlling this process is not known. In order to study the involvement of the mitochondrial apoptotic pathway in M. tuberculosis-induced apoptosis, we analysed cell death in M. tuberculosis-infected embryonic fibroblasts (MEFs) derived from different knockout mice for genes involved in this route. We found that apoptosis induced by M. tuberculosis is abrogated in the absence of Bak and Bax, caspase 9 or the executioner caspases 3 and 7. Notably, we show that MEF deficient in the BH3-only BCL-2-interacting mediator of cell death (Bim) protein were also resistant to this process. The relevance of these results has been confirmed in the mouse macrophage cell line J774, where cell transfection with siRNA targeting Bim impaired apoptosis induced by virulent mycobacteria. Notably, only infection with a virulent strain, but not with attenuated ESX-1-defective strains, such as Bacillus Calmette-Guerin and live-attenuated M. tuberculosis vaccine strain MTBVAC, induced Bim upregulation and apoptosis, probably implicating virulence factor early secreted antigenic target 6-kDa protein in this process. Our results suggest that Bim upregulation and apoptosis is mediated by the p38MAPK-dependent pathway. Our findings show that Bim is a master regulator of apoptosis induced by M. tuberculosis.
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影响因子：
6.7
作者：
Astarie-Dequeker C;Le Guyader L;Malaga W;Seaphanh FK;Chalut C;Lopez A;Guilhot C
通讯作者：
Guilhot C
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3.7
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通讯作者：
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作者：
Hsu, SY;Lin, P;Hsueh, AJW
通讯作者：
Hsueh, AJW