Mycobacterium tuberculosis Mce3C promotes mycobacteria entry into macrophages through activation of β2 integrin-mediated signalling pathway.
Mycobacterium tuberculosis Mce3C promotes mycobacteria entry into macrophages through activation of β2 integrin-mediated signalling pathway.
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结核分枝杆菌 Mce3C 通过激活 β2 整合素介导的信号通路促进分枝杆菌进入巨噬细胞
DOI：
10.1111/cmi.12800
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发表时间：
2017
影响因子：
3.4
通讯作者：
Cui Hua Liu
中科院分区：
文献类型：
--
作者：
Yong Zhang;Jie Li;Bingxi Li;Jing Wang;Cui Hua Liu
通过兼性细胞内病原体结核分枝杆菌（Mtb）建立感染需要粘附于巨噬细胞并被巨噬细胞内化。然而，Mtb用于进入巨噬细胞的效应分子仍有待充分理解。哺乳动物细胞进入（Mce）蛋白在促进分枝杆菌内化到哺乳动物细胞中发挥重要作用。在这里，我们将Mtb Mce3C表征为一种新的分枝杆菌表面蛋白，可以以RGD基序依赖性方式促进分枝杆菌粘附和侵袭巨噬细胞。然后，我们进一步证明了β2整合素是Mce3C介导的细胞进入所必需的。此外，我们发现Mce3C的结合募集β2整合素依赖性信号转导衔接子，并在分枝杆菌侵袭部位诱导局部肌动蛋白重排。通过使用特异性抗体和药理学抑制剂，我们进一步证明了Src家族酪氨酸激酶、脾酪氨酸激酶、Vav、Rho和Rho相关激酶参与Mce3C介导的分枝杆菌侵袭。我们的研究结果揭示了Mtb Mce3C利用整合素介导的Mce信号级联的新机制，为开发抗Mtb感染的疗法提供了潜在靶点。
Establishment of infection by facultative intracellular pathogenMycobacterium tuberculosis(Mtb) requires adherence to and internalisation by macrophages. However, the effector molecules exploited by Mtb for entry into macrophages remain to be fully understood. The mammalian cell entry (Mce) proteins play an essential role in facilitating the internalisation of mycobacteria into mammalian cells. Here, we characterized Mtb Mce3C as a new mycobacterial surface protein that could promote mycobacterial adhesion to and invasion of macrophages in an RGD motif‐dependent manner. We then further demonstrated that β2 integrin was required for Mce3C‐mediated cell entry. In addition, we found that binding of Mce3C recruited β2 integrin‐dependent signalling adaptors and induced local actin rearrangement at the site of mycobacterial invasion. By using specific antibodies and pharmacological inhibitors, we further demonstrated the involvement of Src‐family tyrosine kinases, spleen tyrosine kinase, Vav, Rho, and Rho‐associated kinase in Mce3C‐mediated mycobacterial invasion. Our results reveal a novel mechanism by which Mtb Mce3C exploits integrin‐mediated signalling cascade for Mce, providing potential targets for the development of therapies against Mtb infection.