Yersinia controls type III effector delivery into host cells by modulating Rho activity
Yersinia controls type III effector delivery into host cells by modulating Rho activity
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DOI：
10.1371/journal.ppat.0040003
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发表时间：
2008-01-01
期刊：
影响因子：
6.7
通讯作者：
Viboud, Gloria I.
中科院分区：
文献类型：
--
作者：
Mejia, Edison;Bliska, James B.;Viboud, Gloria I.
假结核耶尔森菌与β1整合素受体结合，并使用III型分泌蛋白YopB和YopD来引入毛孔并将Yop效应器直接转移到宿主细胞中。假结核杆菌缺乏抑制Rho GTP酶的效应物，YopE和YopT，具有很高的成孔活性。在这里，我们提出的证据表明，假结核杆菌选择性地调节Rho活性以诱导细胞变化，从而控制气孔形成和效应器移位。抑制肌动蛋白聚合减少了感染假结核杆菌的HeLa细胞中的孔形成和YopE转位。艰难梭菌毒素B处理使Rho、Rac和Cdc42失活，抑制了感染HeLa细胞中的孔形成和YopE转位。表达显性阴性形式的RAC不会减少感染致孔菌株YopEHJT(-)的HeLa细胞对膜不渗透染料的摄取。同样，RAC抑制剂NSC23766虽然有效地阻止了RAC依赖的细菌的摄取，但并没有减少孔的形成或易位。相比之下，肉毒杆菌C3有效地减少了毛孔的形成和易位，暗示Rho A、B和/或C参与了YOP传递的控制。YopE易位是一种与β1整合素结合但不能有效地通过受体转导信号的invasin突变体(Y.假性结核杆菌invD911E)。干扰β1整合素信号通路，通过抑制Src激酶活性，对YopE易位产生负面影响。此外，假结核杆菌感染激活Rho的机制依赖于YopB和高亲和力细菌与β1整合素受体的相互作用。我们认为，由YopB/YopD转运子和β1整合素受体结合所触发的信号介导的Rho激活，刺激肌动蛋白聚合并激活转位过程，一旦YOPs被转位，YopE或YopT的作用就终止了YOPs的输送，防止了孔的形成。
Yersinia pseudotuberculosis binds to beta 1 integrin receptors, and uses the type III secretion proteins YopB and YopD to introduce pores and to translocate Yop effectors directly into host cells. Y. pseudotuberculosis lacking effectors that inhibit Rho GTPases, YopE and YopT, have high pore forming activity. Here, we present evidence that Y. pseudotuberculosis selectively modulates Rho activity to induce cellular changes that control pore formation and effector translocation. Inhibition of actin polymerization decreased pore formation and YopE translocation in HeLa cells infected with Y. pseudotuberculosis. Inactivation of Rho, Rac, and Cdc42 by treatment with Clostridium difficile toxin B inhibited pore formation and YopE translocation in infected HeLa cells. Expression of a dominant negative form of Rac did not reduce the uptake of membrane impermeable dyes in HeLa cells infected with a pore forming strain YopEHJT(-). Similarly, the Rac inhibitor NSC23766 did not decrease pore formation or translocation, although it efficiently hindered Rac-dependent bacterial uptake. In contrast, C. botulinum C3 potently reduced pore formation and translocation, implicating Rho A, B, and/or C in the control of the Yop delivery. An invasin mutant (Y. pseudotuberculosis invD911E) that binds to beta 1 integrins, but inefficiently transduces signals through the receptors, was defective for YopE translocation. Interfering with the beta 1 integrin signaling pathway, by inhibiting Src kinase activity, negatively affected YopE translocation. Additionally, Y. pseudotuberculosis infection activated Rho by a mechanism that was dependent on YopB and on high affinity bacteria interaction with beta 1 integrin receptors. We propose that Rho activation, mediated by signals triggered by the YopB/YopD translocon and from engagement of beta 1 integrin receptors, stimulates actin polymerization and activates the translocation process, and that once the Yops are translocated, the action of YopE or YopT terminate delivery of Yops and prevents pore formation.