Biozentrum, University of Basel, Klingelbergstrasse 50/70, Basel, Switzerland.
Cell Signal. 2011 Jul;23(7):1188-96. doi: 10.1016/j.cellsig.2011.03.006. Epub 2011 Mar 21.
Shigella flexneri type III secreted effector OspF harbors a phosphothreonine lyase activity that irreversibly dephosphorylates MAP kinases (MAPKs) p38 and ERK in infected epithelial cells and thereby, dampens innate immunity. Whereas this activity has been well characterized, the impact of OspF on other host signaling pathways that control inflammation was unknown. Here we report that OspF potentiates the activation of the MAPK JNK and the transcription factor NF-κB during S. flexneri infection. This unexpected effect of OspF was dependent on the phosphothreonine lyase activity of OspF on p38, and resulted from the disruption of a negative feedback loop regulation between p38 and TGF-beta activated kinase 1 (TAK1), mediated via the phosphorylation of TAK1-binding protein 1. Interestingly, potentiated JNK activation was not associated with enhanced c-Jun signaling as OspF also inhibits c-Jun expression at the transcriptional level. Altogether, our data reveal the impact of OspF on the activation of NF-κB, JNK and c-Jun, and demonstrate the existence of a negative feedback loop regulation between p38 and TAK1 during S. flexneri infection. Furthermore, this study validates the use of bacterial effectors as molecular tools to identify the crosstalks that connect important host signaling pathways induced upon bacterial infection.
福氏志贺氏菌 III 型分泌效应物 OspF 具有磷酸苏氨酸裂合酶活性，可不可逆地使感染上皮细胞中的 MAP 激酶（MAPKs）p38 和 ERK 去磷酸化，从而抑制先天免疫。虽然这种活性已经得到了很好的描述，但 OspF 对控制炎症的其他宿主信号通路的影响尚不清楚。在这里，我们报告 OspF 增强了 MAPK JNK 和转录因子 NF-κB 在福氏志贺氏菌感染期间的激活。OspF 的这种意外作用依赖于 OspF 对 p38 的磷酸苏氨酸裂合酶活性，并且源自 p38 和 TGF-β激活激酶 1（TAK1）之间负反馈回路调节的破坏，这是通过 TAK1 结合蛋白 1 的磷酸化介导的。有趣的是，增强的 JNK 激活与增强的 c-Jun 信号无关，因为 OspF 还在转录水平上抑制 c-Jun 表达。总的来说，我们的数据揭示了 OspF 对 NF-κB、JNK 和 c-Jun 激活的影响，并证明了在福氏志贺氏菌感染期间 p38 和 TAK1 之间存在负反馈回路调节。此外，这项研究验证了将细菌效应物用作分子工具来识别连接细菌感染诱导的重要宿主信号通路的串扰的用途。
