Apoptosis triggered by Rv1818c, a PE family gene from Mycobacterium tuberculosis is regulated by mitochondrial intermediates in T cells
Apoptosis triggered by Rv1818c, a PE family gene from Mycobacterium tuberculosis is regulated by mitochondrial intermediates in T cells
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DOI：
10.1016/j.micinf.2006.11.013
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发表时间：
2007-03-01
影响因子：
5.8
通讯作者：
Mohammad, Saleemulla
中科院分区：
文献类型：
--
作者：
Balaji, Kithiganahalli N.;Goyal, Girija;Mohammad, Saleemulla
结核分枝杆菌PE家族基因Rv 1818 c的异位表达引发哺乳动物Jurkat T细胞的凋亡，其被抗凋亡蛋白Bcl-2阻断。虽然没有观察到完全重叠，但异位表达的Rv 1818 c的细胞池的相当大的比例定位于线粒体。然而，即使Rv 1818 c蛋白诱导Jurkat T细胞的凋亡，重组Rv 1818 c也不触发细胞色素c从分离的线粒体的释放。Rv 1818 c诱导的细胞凋亡被广谱caspase抑制肽zVAD-FMK阻断。出乎意料的是，Rv 1818 c诱导的细胞凋亡在半胱天冬酶-8（JI 9.2）缺陷的Jurkat亚克隆中或在半胱天冬酶-9功能被抑制或半胱天冬酶-9表达被siRNA降低的细胞中没有被阻断，这与这些半胱天冬酶在Rv 1818 c诱导的细胞凋亡信号传导中的中心作用相反。消耗线粒体蛋白Smac/DIABLO的细胞库显著减少细胞凋亡，这与线粒体参与该死亡途径一致。我们目前的证据表明，Rv 1818 c诱导的细胞凋亡被阻断的共同转染的内源性半胱天冬酶激活抑制剂，XIAP在T细胞。此外，Rv 1818 c通过M分泌的外泌体释放到细胞外环境中。结核感染BM-DC和巨噬细胞。此外，细胞外Rv 1818 c蛋白可以在与感染的BM-DC共培养的T细胞中检测到。综上所述，这些数据表明，Rv 1818 c诱导的凋亡信号可能部分由T细胞中的半胱天冬酶的Smac依赖性激活调节。(c)2006年爱思唯尔马森SAS。All rights reserved.
Ectopic expression of the Mycobacterium tuberculosis PE-family gene Rv1818c, triggers apoptosis in the mammalian Jurkat T cells, which is blocked by anti-apoptotic protein Bcl-2. Although complete overlap is not observed, a considerable proportion of cellular pools of ectopically expressed Rv1818c localizes to mitochondria. However, recombinant Rv1818c does not trigger release of cytochrome c from isolated mitochondria even though Rv1818c protein induced apoptosis of Jurkat T cells. Apoptosis induced by Rv1818c is blocked by the broad-spectrum caspase inhibitory peptide zVAD-FMK. Unexpectedly, Rv1818c-induced apoptosis is not blocked in a Jurkat sub-clone deficient for caspase-8 (JI 9.2) or in cells where caspase-9 function is inhibited or expression of caspase-9 reduced by siRNA, arguing against a central role for these caspases in Rv1818c-induced apoptotic signaling. Depleting cellular pools of the mitochondrial protein Smac/DIABLO substantially reduces apoptosis consistent with mitochondrial involvement in this death pathway. We present evidence that Rv1818c-induced apoptosis is blocked by the co-transfection of an endogenous inhibitor of caspase activation, XIAP in T cells. Additionally, Rv1818c is released into extracellular environment via exosomes secreted by M. tuberculosis infected BM-DC's and macrophages. Furthermore, the extracellular Rv1818c protein can be detected in T cells co-cultured with infected BM-DC's. Taken together, these data suggest that Rv1818c-induced apoptotic signaling is likely regulated in part by the Smac-dependent activation of caspases in T cells. (c) 2006 Elsevier Masson SAS. All rights reserved.