Yersinia pseudotuberculosis Effector YopJ Subverts the Nod2/RICK/TAK1 Pathway and Activates Caspase-1 to Induce Intestinal Barrier Dysfunction
Yersinia pseudotuberculosis Effector YopJ Subverts the Nod2/RICK/TAK1 Pathway and Activates Caspase-1 to Induce Intestinal Barrier Dysfunction
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DOI：
10.1016/j.chom.2012.02.009
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发表时间：
2012-04-19
影响因子：
30.3
通讯作者：
Hugot, Jean-Pierre
中科院分区：
文献类型：
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作者：
Meinzer, Ulrich;Barreau, Frederick;Hugot, Jean-Pierre
假结核耶尔森氏菌是一种肠道致病菌，它会破坏肠道屏障，并通过肠道相关淋巴组织和派尔氏集结 (PP) 侵入宿主。我们发现，假结核杆菌效应子 YopJ 通过破坏先天免疫受体 Nod2 的信号传导来诱导肠道屏障功能障碍，这种表型可以通过用 Nod2 配体胞壁酰二肽预处理来逆转。 YopJ（而非催化失活突变体 YopJ(C172A)）乙酰化 RICK 和 TAK1 激酶（Nod2 信号传导的中心介质）激活环中的关键位点，并降低 Nod2 与 RICK 的亲和力。与此同时，Nod2 与 caspase-1 相互作用并激活 caspase-1，导致 IL-1 beta 水平增加。最后，PP 中的 IL-1 beta 在诱导肠道屏障功能障碍中发挥着重要作用。因此，YopJ 通过利用粘膜炎症反应来改变肠道通透性并促进耶尔森氏菌和共生细菌的传播。
Yersinia pseudotuberculosis is an enteropathogenic bacteria that disrupts the intestinal barrier and invades its host through gut-associated lymphoid tissue and Peyer's patches (PP). We show that the Y. pseudotuberculosis effector YopJ induces intestinal barrier dysfunction by subverting signaling of the innate immune receptor Nod2, a phenotype that can be reversed by pretreating with the Nod2 ligand muramyl-dipeptide. YopJ, but not the catalytically inactive mutant YopJ(C172A), acetylates critical sites in the activation loops of the RICK and TAK1 kinases, which are central mediators of Nod2 signaling, and decreases the affinity of Nod2 for RICK. Concomitantly, Nod2 interacts with and activates caspase-1, resulting in increased levels of IL-1 beta. Finally, IL-1 beta within PP plays an essential role in inducing intestinal barrier dysfunction. Thus, YopJ alters intestinal permeability and promotes the dissemination of Yersinia as well as commensal bacteria by exploiting the mucosal inflammatory response.