Department of Cell and Developmental Biology, Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem, Israel.
Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
Infect Immun. 2018 Sep 21;86(10). doi: 10.1128/IAI.00303-18. Print 2018 Oct.
Enteropathogenic (EPEC) belongs to a group of enteric human pathogens known as attaching-and-effacing (A/E) pathogens, which utilize a type III secretion system (T3SS) to translocate a battery of effector proteins from their own cytoplasm into host intestinal epithelial cells. Here we identified EspH to be an effector that prompts the recruitment of the tetraspanin CD81 to infection sites. EspH was also shown to be an effector that suppresses the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (Erk) signaling pathway at longer infection times. The inhibitory effect was abrogated upon deletion of the last 38 amino acids located at the C terminus of the protein. The efficacy of EspH-dependent Erk suppression was higher in CD81-deficient cells, suggesting that CD81 may act as a positive regulator of Erk, counteracting Erk suppression by EspH. EspH was found within CD81 microdomains soon after infection but was largely excluded from these domains at a later time. Based on our results, we propose a mechanism whereby CD81 is initially recruited to infection sites in response to EspH translocation. At a later stage, EspH moves out of the CD81 clusters to facilitate effective Erk inhibition. Moreover, EspH selectively inhibits the tumor necrosis factor alpha (TNF-α)-induced Erk signaling pathway. Since Erk and TNF-α have been implicated in innate immunity and cell survival, our studies suggest a novel mechanism by which EPEC suppresses these processes to promote its own colonization and survival in the infected gut.
肠致病性大肠杆菌（EPEC）属于一组被称为附着和破坏（A/E）病原体的肠道人类病原体，它们利用 III 型分泌系统（T3SS）将一系列效应蛋白从细胞质转运到宿主肠道上皮细胞中。在这里，我们确定 EspH 是一种效应蛋白，可促使 Tetraspanin CD81 募集到感染部位。还表明 EspH 是一种效应蛋白，可在较长的感染时间内抑制丝裂原激活的蛋白激酶（MAPK）/细胞外信号调节激酶（Erk）信号通路。在删除位于蛋白质 C 末端的最后 38 个氨基酸后，抑制作用被消除。在 CD81 缺陷细胞中，EspH 依赖性 Erk 抑制的效果更高，这表明 CD81 可能作为 Erk 的正调节剂，抵消 EspH 对 Erk 的抑制作用。EspH 在感染后不久就存在于 CD81 微区中，但在稍后的时间内很大程度上被排除在这些区域之外。根据我们的结果，我们提出了一种机制，即 CD81 最初被募集到感染部位以响应 EspH 的易位。在后期，EspH 从 CD81 簇中移出，以促进有效的 Erk 抑制。此外，EspH 选择性抑制肿瘤坏死因子-α（TNF-α）诱导的 Erk 信号通路。由于 Erk 和 TNF-α 已被牵连到先天免疫和细胞存活中，我们的研究表明，EPEC 抑制这些过程以促进其自身在感染肠道中的定植和存活的新机制。
