Secreted Mycobacterium tuberculosis Rv3654c and Rv3655c proteins participate in the suppression of macrophage apoptosis.
Secreted Mycobacterium tuberculosis Rv3654c and Rv3655c proteins participate in the suppression of macrophage apoptosis.
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DOI：
10.1371/journal.pone.0010474
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发表时间：
2010-05-04
期刊：
影响因子：
3.7
通讯作者：
Bermudez LE
中科院分区：
文献类型：
--
作者：
Danelishvili L;Yamazaki Y;Selker J;Bermudez LE
结核分枝杆菌对巨噬细胞凋亡的抑制被认为是其避免宿主防御的毒力机制之一。探讨结核分枝杆菌H37Rv抑制细胞凋亡和逃避人巨噬细胞杀伤的机制。转座子突变体库的筛选发现了几种突变体，与野生型细菌相比，它们抑制巨噬细胞凋亡的能力受损。在鉴定的基因中，Rv3659c （31G12突变体）属于IV型菌毛的操纵子。Rv3654c和Rv3655c两种被认为是由7个基因操纵子组成的蛋白分泌到巨噬细胞细胞质中，通过阻断外源性途径抑制细胞凋亡。与细胞外环境的表达水平相比，当细菌在巨噬细胞内时，操纵子的表达量很高。Rv3654c识别聚嘧啶束结合蛋白相关剪接因子（PSF）并切割它，降低caspase-8的可用性。虽然结核分枝杆菌通过外源性途径抑制细胞凋亡，但病原体似乎不影响内在途径。药物使内在途径失活可影响结核分枝杆菌并诱导细胞坏死。同样，siRNA灭活PSF显著降低巨噬细胞中caspase-8的水平。虽然结核分枝杆菌抑制细胞凋亡的外在途径，但它似乎激活了导致巨噬细胞坏死的内在途径，作为一种潜在的退出策略。
Inhibition of macrophage apoptosis by Mycobacterium tuberculosis has been proposed as one of the virulence mechanisms whereby the pathogen avoids the host defense. The mechanisms by which M. tuberculosis H37Rv strain suppress apoptosis and escapes human macrophage killing was investigated. The screening of a transposon mutant bank identified several mutants, which, in contrast to the wild-type bacterium, had impaired ability to inhibit apoptosis of macrophages. Among the identified genes, Rv3659c (31G12 mutant) belongs to an operon reminiscent of type IV pili. The Rv3654c and Rv3655c putative proteins in a seven-gene operon are secreted into the macrophage cytoplasm and suppress apoptosis by blocking the extrinsic pathway. The operon is highly expressed when the bacterium is within macrophages, compared to the expression level in the extracellular environment. Rv3654c recognizes the polypyrimidine tract binding Protein-associated Splicing Factor (PSF) and cleaves it, diminishing the availability of caspase-8. While M. tuberculosis inhibits apoptosis by the extrinsic pathway, the pathogen does not appear to affect the intrinsic pathway. Inactivation of the intrinsic pathway by pharmacologic agents afftects M. tuberculosis and induces cell necrosis. Likewise, inactivation of PSF by siRNA significantly decreased the level of caspase-8 in macrophages. While M. tuberculosis inhibits the extrinsic pathway of apoptosis, it appears to activate the intrinsic pathway leading to macrophage necrosis as a potential exit strategy.
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DOI：
10.1084/jem.20080767
发表时间：
2008-11-24
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Chen M;Divangahi M;Gan H;Shin DS;Hong S;Lee DM;Serhan CN;Behar SM;Remold HG
通讯作者：
Remold HG
影响因子：
4.4
作者：
Chen, Minjian;Gan, Huixian;Remold, Heinz G.
通讯作者：
Remold, Heinz G.
DOI：
10.1073/pnas.0610746104
发表时间：
2007-06-26
影响因子：
11.1
作者：
Danelishvili, Lia;Wu, Martin;Bermudez, Luiz E.
通讯作者：
Bermudez, Luiz E.
影响因子：
2.1
作者：
Danelishvili, L;Poort, MJ;Bermudez, LE
通讯作者：
Bermudez, LE
影响因子：
64.5
作者：
Boldin, MP;Goncharov, TM;Wallach, D
通讯作者：
Wallach, D