Shigella Effector OspB Activates mTORC1 in a Manner That Depends on IQGAP1 and Promotes Cell Proliferation
Shigella Effector OspB Activates mTORC1 in a Manner That Depends on IQGAP1 and Promotes Cell Proliferation
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DOI：
10.1371/journal.ppat.1005200
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发表时间：
2015-10-01
期刊：
影响因子：
6.7
通讯作者：
Goldberg, Marcia B.
中科院分区：
文献类型：
--
作者：
Lu, Richard;Herrera, Bobby Brooke;Goldberg, Marcia B.
细胞内细菌病原体志贺氏菌感染并通过人类肠上皮传播。志贺氏菌递送到细胞中的效应蛋白通过调节多种宿主功能促进感染。我们证明了效应蛋白OspB直接与支架蛋白IQGAP 1相互作用，并且在感染期间OspB或IQGAP 1的缺失导致更大的S.弗氏菌通过细胞单层扩散。我们表明，对细菌传播区域的影响是由于OspB触发感染灶周围的细胞增殖增加，从而取代感染灶内死亡的一些细胞并限制细菌传播区域。我们证明，OspB增强细胞增殖的结果从激活mTORC 1，细胞生长的主调节器，并被mTORC 1特异性抑制剂雷帕霉素阻断。mTORC 1的OspB激活及其对细胞增殖和细菌传播的影响取决于IQGAP 1。我们的研究结果确定OspB作为mTORC 1和mTORC 1依赖的细胞增殖的调节剂在S. flexneri感染，并确定IQGAP 1在mTORC 1信号传导中的作用。他们还提出了IQGAP 1作为OspB-mTORC 1信号复合物组装支架的可能性。
The intracellular bacterial pathogen Shigella infects and spreads through the human intestinal epithelium. Effector proteins delivered by Shigella into cells promote infection by modulating diverse host functions. We demonstrate that the effector protein OspB interacts directly with the scaffolding protein IQGAP1, and that the absence of either OspB or IQGAP1 during infection leads to larger areas of S. flexneri spread through cell monolayers. We show that the effect on the area of bacterial spread is due to OspB triggering increased cell proliferation at the periphery of infected foci, thereby replacing some of the cells that die within infected foci and restricting the area of bacterial spread. We demonstrate that OspB enhancement of cell proliferation results from activation of mTORC1, a master regulator of cell growth, and is blocked by the mTORC1-specific inhibitor rapamycin. OspB activation of mTORC1, and its effects on cell proliferation and bacterial spread, depends on IQGAP1. Our results identify OspB as a regulator of mTORC1 and mTORC1-dependent cell proliferation early during S. flexneri infection and establish a role for IQGAP1 in mTORC1 signaling. They also raise the possibility that IQGAP1 serves as a scaffold for the assembly of an OspB-mTORC1 signaling complex.