Matsuzawa Takeshi, Kuwae Asaomi, Yoshida Sei, Sasakawa Chihiro, Abe Akio
Department of Infection Control and Immunology, Laboratory of Bacterial Infection, Kitasato Institute for Life Sciences, Kitasato University, Shirokane, Minato-ku, Tokyo, Japan.
EMBO J. 2004 Sep 1;23(17):3570-82. doi: 10.1038/sj.emboj.7600359. Epub 2004 Aug 19.
Enteropathogenic Escherichia coli delivers a subset of effectors into host cells via a type III secretion system, and this step is required for the progression of disease. Here, we show that the type III effectors, EspG and its homolog Orf3, trigger actin stress fiber formation and the destruction of the microtubule networks beneath adherent bacteria. Both effectors were shown to possess the ability to interact with tubulins, and to stimulate microtubule destabilization in vitro. A recent study showed that microtubule-bound GEF-H1, a RhoA-specific guanine nucleotide exchange factor, was converted to its active form by microtubule destabilization, and this sequence of events resulted in RhoA stimulation. Indeed, EspG- and Orf3-induced stress fiber formation was inhibited by the expression of dominant-negative forms of GEF-H1 and RhoA, but not of Rac1 and Cdc42, and by treatment with a ROCK inhibitor. These results indicate that the impact of EspG/Orf3 on microtubule networks triggers the activation of the RhoA-ROCK signaling pathway via GEF-H1 activity. This report reveals for the first time that a pathogen can exploit the host factor GEF-H1.
肠道致病性大肠杆菌通过III型分泌系统将一部分效应蛋白输送到宿主细胞中，这一步骤是疾病进展所必需的。在此，我们表明III型效应蛋白EspG及其同源物Orf3会引发肌动蛋白应激纤维的形成以及粘附细菌下方微管网络的破坏。这两种效应蛋白均显示出与微管蛋白相互作用的能力，并在体外刺激微管去稳定化。最近的一项研究表明，与微管结合的GEF-H1（一种RhoA特异性鸟嘌呤核苷酸交换因子）会因微管去稳定化而转变为其活性形式，并且这一系列事件会导致RhoA的激活。实际上，EspG和Orf3诱导的应激纤维形成受到GEF-H1和RhoA显性负性形式的表达抑制，但不受Rac1和Cdc42的抑制，并且受到ROCK抑制剂处理的抑制。这些结果表明，EspG/Orf3对微管网络的影响通过GEF-H1活性触发了RhoA-ROCK信号通路的激活。本报告首次揭示了病原体可以利用宿主因子GEF-H1。
