The Chlamydia trachomatis secreted effector TmeA hijacks the N-WASP-ARP2/3 actin remodeling axis to facilitate cellular invasion.
The Chlamydia trachomatis secreted effector TmeA hijacks the N-WASP-ARP2/3 actin remodeling axis to facilitate cellular invasion.
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DOI：
10.1371/journal.ppat.1008878
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发表时间：
2020-09
期刊：
影响因子：
6.7
通讯作者：
Weber MM
中科院分区：
文献类型：
--
作者：
Faris R;McCullough A;Andersen SE;Moninger TO;Weber MM
沙眼衣原体作为一种专性胞内病原体，其侵入宿主细胞是其增殖的关键。虽然这一基本过程的机制基础仍然不明确，但预计涉及将预包装的效应蛋白递送到宿主细胞中，从而引发质膜重塑和细胞骨架重组。分泌的效应蛋白TmeA和TarP作为细胞侵袭和细菌发病机制的假定关键调节剂已经变得突出。虽然一些研究已经开始解开TarP的假定功能的分子细节，TmeA在宿主细胞入侵过程中的生理功能是未知的。在这里，我们表明，TmeA采用分子模拟结合到GTdR结合域的N-WASP，这导致在招聘的肌动蛋白分支ARP 2/3复合体的网站衣原体条目。电子显微镜显示，TmeA突变体是不足的丝状伪足捕获，表明TmeA/N-WASP相互作用最终调节宿主细胞质膜重塑衣原体进入所必需的事件。重要的是，虽然TmeA和TarP都是有效的宿主细胞入侵所必需的，但我们表明这些效应子靶向最终聚集在ARP 2/3复合物激活上的不同途径。根据这一观察，我们发现双突变体患有严重的进入缺陷，几乎与ARP 3被化学抑制或敲除时观察到的相同。总的来说，我们的研究强调了TmeA和TarP作为衣原体入侵的重要调节因子，通过不同的信号平台调节ARP 2/3复合物，导致质膜重塑事件，这对病原体摄取至关重要。沙眼衣原体是沙眼的病原体，也是世界范围内最常见的细菌性传播感染。作为一种专性胞内病原体，细菌的增殖只发生在宿主细胞的范围内，因此入侵是感染过程中的关键步骤。虽然已知分泌的效应蛋白TmeA对于入侵和细菌发病机理是必需的，但TmeA如何促进入侵以前是未知的。在这里，我们表明，TmeA结合到GTdR结合结构域的成核促进因子N-WASP和他们的相互作用是必要的招聘的ARP 2/3复合物的细菌进入病灶。此外，我们的研究表明，虽然分泌的效应蛋白TarP也参与招募ARP 2/3复合物，但它在与N-WASP不同的途径中发挥作用。总的来说，我们的研究表明，TmeA和TarP靶向不同的细胞信号传导途径，这些途径聚集在ARP 2/3复合物上，ARP 2/3复合物是病原体摄取的关键调节因子。
As an obligate intracellular pathogen, host cell invasion is paramount to Chlamydia trachomatis proliferation. While the mechanistic underpinnings of this essential process remain ill-defined, it is predicted to involve delivery of prepackaged effector proteins into the host cell that trigger plasma membrane remodeling and cytoskeletal reorganization. The secreted effector proteins TmeA and TarP, have risen to prominence as putative key regulators of cellular invasion and bacterial pathogenesis. Although several studies have begun to unravel molecular details underlying the putative function of TarP, the physiological function of TmeA during host cell invasion is unknown. Here, we show that TmeA employs molecular mimicry to bind to the GTPase binding domain of N-WASP, which results in recruitment of the actin branching ARP2/3 complex to the site of chlamydial entry. Electron microscopy revealed that TmeA mutants are deficient in filopodia capture, suggesting that TmeA/N-WASP interactions ultimately modulate host cell plasma membrane remodeling events necessary for chlamydial entry. Importantly, while both TmeA and TarP are necessary for effective host cell invasion, we show that these effectors target distinct pathways that ultimately converge on activation of the ARP2/3 complex. In line with this observation, we show that a double mutant suffers from a severe entry defect nearly identical to that observed when ARP3 is chemically inhibited or knocked down. Collectively, our study highlights both TmeA and TarP as essential regulators of chlamydial invasion that modulate the ARP2/3 complex through distinct signaling platforms, resulting in plasma membrane remodeling events that are essential for pathogen uptake. Chlamydia trachomatis is the etiological agent of trachoma and is the most common bacterial sexually transmitted infection worldwide. As an obligate intracellular pathogen, bacterial proliferation only occurs within the confines of a host cell, thus invasion is the critical step in the infection process. While the secreted effector protein TmeA is known to be essential for invasion and bacterial pathogenesis, how TmeA promotes invasion was previously unknown. Here we show that TmeA binds to the GTPase binding domain of the nucleation promoting factor N-WASP and their interaction is necessary for recruitment of the ARP2/3 complex to the bacterial entry foci. Moreover, our study shows that while the secreted effector protein TarP is also involved in recruiting the ARP2/3 complex, it functions in a pathway that is distinct from N-WASP. Collectively, our study suggests that TmeA and TarP target distinct cell signaling pathways that converge on the ARP2/3 complex, a key regulator of pathogen uptake.
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影响因子：
3.6
作者：
Hower S;Wolf K;Fields KA
通讯作者：
Fields KA
DOI：
10.1038/nrm2867
发表时间：
2010-04
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
6.7
作者：
Chen YS;Bastidas RJ;Saka HA;Carpenter VK;Richards KL;Plano GV;Valdivia RH
通讯作者：
Valdivia RH
影响因子：
3.6
作者：
Fields, KA;Mead, DJ;Hackstadt, T
通讯作者：
Hackstadt, T
DOI：
10.1073/pnas.0603044103
发表时间：
2006-10-17
影响因子：
11.1
作者：
Jewett, Travis J.;Fischer, Elizabeth R.;Hackstadt, Ted
通讯作者：
Hackstadt, Ted