Diverse bacterial pathogens employ effector delivery systems to disrupt vital cellular processes in the host (N. M. Alto and K. Orth, Cold Spring Harbor Perspect Biol 4:a006114, 2012, https://doi.org/10.1101/cshperspect.a006114). The type III secretion system 1 of the marine pathogen Vibrio parahaemolyticus utilizes the sequential action of four effectors to induce a rapid, proinflammatory cell death uniquely characterized by a prosurvival host transcriptional response (D. L. Burdette, M. L. Yarbrough, A Orvedahl, C. J. Gilpin, and K. Orth, Proc Natl Acad Sci USA 105:12497–12502, 2008, https://doi.org/10.1073/pnas.0802773105; N. J. De Nisco, M. Kanchwala, P. Li, J. Fernandez, C. Xing, and K. Orth, Sci Signal 10:eaa14501, 2017, https://doi.org/10.1126/scisignal.aal4501). Herein, we show that this prosurvival response is caused by the action of the channel-forming effector VopQ that targets the host V-ATPase, resulting in lysosomal deacidification and inhibition of lysosome-autophagosome fusion. Recent structural studies have shown how VopQ interacts with the V-ATPase and, while in the ER, a V-ATPase assembly intermediate can interact with VopQ, causing a disruption in membrane integrity. Additionally, we observed that VopQ-mediated disruption of the V-ATPase activates the IRE1 branch of the unfolded protein response (UPR), resulting in an IRE1-dependent activation of ERK1/2 MAPK signaling. We also find that this early VopQ-dependent induction of ERK1/2 phosphorylation is terminated by the VopS-mediated inhibitory AMPylation of Rho GTPase signaling. Since VopS dampens VopQ-induced IRE1-dependent ERK1/2 activation, we propose that IRE1 activates ERK1/2 phosphorylation at or above the level of Rho GTPases. This study illustrates how temporally induced effectors can work as in tandem as agonist/antagonist to manipulate host signaling and reveals new connections between V-ATPase function, UPR, and MAPK signaling.

中文翻译：

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弧菌激动剂-拮抗剂效应器对对 IRE1 依赖性 MAPK 信号传导的操纵

多种细菌病原体利用效应传递系统来破坏宿主的重要细胞过程（NM Alto 和 K. Orth，Cold Spring Harbor Perspect Biol 4:a006114, 2012，https://doi.org/10.1101/cshperspect.a006114）。海洋病原体副溶血弧菌的 III 型分泌系统 1利用四个效应子的连续作用来诱导快速的促炎性细胞死亡，其独特的特征是促存活宿主转录反应（DL Burdette、ML Yarbrough、A Orvedahl、CJ Gilpin 和 K . Orth, Proc Natl Acad Sci USA 105:12497–12502, 2008, https://doi.org/10.1073/pnas.0802773105; NJ De Nisco, M. Kanchwala, P. Li, J. Fernandez, C. Xing,和 K. Orth，Sci Signal 10：eaa14501，2017 年，https://doi.org/10.1126/scisignal.aal4501）。在此，我们证明这种促生存反应是由靶向宿主 V-ATP 酶的通道形成效应器 VopQ 的作用引起的，导致溶酶体脱酸并抑制溶酶体-自噬体融合。最近的结构研究表明，VopQ 如何与 V-ATP 酶相互作用，而在内质网中，V-ATP 酶组装中间体可以与 VopQ 相互作用，导致膜完整性破坏。此外，我们观察到 VopQ 介导的 V-ATP 酶破坏激活了未折叠蛋白反应 (UPR) 的 IRE1 分支，导致 ERK1/2 MAPK 信号传导的 IRE1 依赖性激活。我们还发现，这种早期 VopQ 依赖性 ERK1/2 磷酸化诱导被 VopS 介导的 Rho GTPase 信号传导抑制性 AMPylation 终止。由于 VopS 抑制 VopQ 诱导的 IRE1 依赖性 ERK1/2 激活，因此我们认为 IRE1 在 Rho GTPases 水平或以上激活 ERK1/2 磷酸化。这项研究说明了时间诱导效应器如何与激动剂/拮抗剂一起协同作用来操纵宿主信号传导，并揭示了 V-ATP 酶功能、UPR 和 MAPK 信号传导之间的新联系。