Manipulation of IRE1-Dependent MAPK Signaling by a Vibrio Agonist-Antagonist Effector Pair.
Manipulation of IRE1-Dependent MAPK Signaling by a Vibrio Agonist-Antagonist Effector Pair.
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弧菌激动剂-拮抗剂效应对ire1依赖性MAPK信号的调控
DOI：
10.1128/msystems.00872-20
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发表时间：
2021-02-09
期刊：
影响因子：
6.4
通讯作者：
Orth K
中科院分区：
文献类型：
--
作者：
De Nisco NJ;Casey AK;Kanchwala M;Lafrance AE;Coskun FS;Kinch LN;Grishin NV;Xing C;Orth K
副溶血性弧菌是一种海产品传播的病原体，编码两种3型分泌系统（T3 SS）。第一个系统T3 SS 1被认为在所有副溶血性弧菌菌株中维持，以维持在环境中的存活，而第二个系统T3 SS 2与人类的临床分离株和疾病有关。不同的细菌病原体采用效应传递系统来破坏宿主中的重要细胞过程（N. M. Alto和K. Orth，冷泉港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利用四种效应物的顺序作用来诱导快速的促炎细胞死亡，其独特特征在于促存活宿主转录应答（D. L. Burdette，M. L. Yarbrough，A Orvedahl，C. Gilpin和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.费尔南德斯，C. Xing和K. Orth，Sci Signal 10：eaa14501，2017，https：//doi.org/10.1126/scisignal.aal4501）。在此，我们表明，这种促生存反应是由通道形成效应VopQ的作用，靶向宿主V-ATP酶，导致溶酶体脱酸和抑制溶酶体-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ER中，V-ATP酶组装中间体可以与VopQ相互作用，导致膜完整性的破坏。此外，我们观察到VopQ介导的V-ATP酶的破坏激活了未折叠蛋白反应（UPR）的IRE 1分支，导致IRE 1依赖的ERK 1/2 MAPK信号转导的激活。我们还发现，这种早期VopQ依赖性的ERK 1/2磷酸化诱导被VopS介导的Rho GT3信号转导的抑制性AMP化终止。由于VopS抑制VopQ诱导的IRE 1依赖性ERK 1/2激活，我们认为IRE 1在Rho GTP酶水平或以上激活ERK 1/2磷酸化。这项研究说明了如何临时诱导的效应器可以串联作为激动剂/拮抗剂来操纵宿主信号，并揭示了V-ATP酶功能，UPR和MAPK信号之间的新联系。副溶血性弧菌是一种海产品传播的病原体，编码两种3型分泌系统（T3 SS）。第一个系统T3 SS 1被认为在所有副溶血性弧菌菌株中维持，以维持在环境中的存活，而第二个系统T3 SS 2与人类的临床分离株和疾病有关。在这里，我们发现第一个系统靶向进化保守的信号系统来操纵宿主细胞，最终在3小时内导致快速，精心策划的细胞死亡。我们已经发现T3 SS 1注入毒性因子，暂时操纵宿主信号传导。在感染的第一个小时内，效应子VopQ首先通过激活宿主存活信号而起作用，同时减少宿主细胞凋亡机制。不到一小时后，另一种效应物VopS逆转了这些信号系统的激活和抑制，最终导致宿主细胞死亡。这项工作提供了病原体如何进化以操纵T3 SS效应子之间的相互作用来调节宿主信号传导途径的例子。
Vibrio parahaemolyticus is a seafood-borne pathogen that encodes two type 3 secretion systems (T3SS). The first system, T3SS1, is thought to be maintained in all strains of V. parahaemolyticus to maintain survival in the environment, whereas the second system, T3SS2, is linked to clinical isolates and disease in humans. 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. IMPORTANCE Vibrio parahaemolyticus is a seafood-borne pathogen that encodes two type 3 secretion systems (T3SS). The first system, T3SS1, is thought to be maintained in all strains of V. parahaemolyticus to maintain survival in the environment, whereas the second system, T3SS2, is linked to clinical isolates and disease in humans. Here, we found that first system targets evolutionarily conserved signaling systems to manipulate host cells, eventually causing a rapid, orchestrated cells death within 3 h. We have found that the T3SS1 injects virulence factors that temporally manipulate host signaling. Within the first hour of infection, the effector VopQ acts first by activating host survival signals while diminishing the host cell apoptotic machinery. Less than an hour later, another effector, VopS, reverses activation and inhibition of these signaling systems, ultimately leading to death of the host cell. This work provides example of how pathogens have evolved to manipulate the interplay between T3SS effectors to regulate host signaling pathways.
影响因子：
7.3
作者：
De Nisco NJ;Kanchwala M;Li P;Fernandez J;Xing C;Orth K
通讯作者：
Orth K