A TNF- and c-Cbl-dependent FLIPS-degradation pathway and its function in Mycobacterium tuberculosis-induced macrophage apoptosis
A TNF- and c-Cbl-dependent FLIPS-degradation pathway and its function in Mycobacterium tuberculosis-induced macrophage apoptosis
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DOI：
10.1038/ni.1754
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发表时间：
2009-08-01
影响因子：
30.5
通讯作者：
Basu, Joyoti
中科院分区：
文献类型：
--
作者：
Kundu, Manikuntala;Pathak, Sushil Kumar;Basu, Joyoti
细胞凋亡是病原性分枝杆菌与宿主巨噬细胞相互作用的中心环节。感染巨噬细胞的半胱天冬酶-8依赖性凋亡，需要激活促分裂原活化蛋白（MAP）激酶p38，降低分枝杆菌的传播。在这里，我们建立了肿瘤坏死因子（TNF）的释放和分枝杆菌介导的巨噬细胞凋亡之间的联系。TNF激活了一条涉及激酶ASK 1、p38和c-Abl的通路，该通路导致FLIPS磷酸化，从而促进其与E3泛素连接酶c-Cbl的相互作用。这种相互作用触发了FLIPS的蛋白酶体降解，从而促进了caspase-8的活化和凋亡。我们的研究结果确定了结核分枝杆菌引发的巨噬细胞死亡所需的一个以前不受重视的信号通路。
Apoptosis is central to the interaction between pathogenic mycobacteria and host macrophages. Caspase-8-dependent apoptosis of infected macrophages, which requires activation of the mitogen-activated protein (MAP) kinase p38, lowers the spread of mycobacteria. Here we establish a link between the release of tumor necrosis factor (TNF) and mycobacteria-mediated macrophage apoptosis. TNF activated a pathway involving the kinases ASK1, p38 and c-Abl. This pathway led to phosphorylation of FLIPS, which facilitated its interaction with the E3 ubiquitin ligase c-Cbl. This interaction triggered proteasomal degradation of FLIPS, which promoted activation of caspase-8 and apoptosis. Our findings identify a previously unappreciated signaling pathway needed for Mycobacterium tuberculosis-triggered macrophage cell death.