Fukazawa Atsuko, Alonso Carmen, Kurachi Kiyotaka, Gupta Sonal, Lesser Cammie F, McCormick Beth Ann, Reinecker Hans-Christian
Department of Medicine, Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
PLoS Pathog. 2008 Nov;4(11):e1000228. doi: 10.1371/journal.ppat.1000228. Epub 2008 Nov 28.
Shigella flexneri has evolved the ability to modify host cell function with intracellular active effectors to overcome the intestinal barrier. The detection of these microbial effectors and the initiation of innate immune responses are critical for rapid mucosal defense activation. The guanine nucleotide exchange factor H1 (GEF-H1) mediates RhoA activation required for cell invasion by the enteroinvasive pathogen Shigella flexneri. Surprisingly, GEF-H1 is requisite for NF-kappaB activation in response to Shigella infection. GEF-H1 interacts with NOD1 and is required for RIP2 dependent NF-kappaB activation by H-Ala-D-gammaGlu-DAP (gammaTriDAP). GEF-H1 is essential for NF-kappaB activation by the Shigella effectors IpgB2 and OspB, which were found to signal in a NOD1 and RhoA Kinase (ROCK) dependent manner. Our results demonstrate that GEF-H1 is a critical component of cellular defenses forming an intracellular sensing system with NOD1 for the detection of microbial effectors during cell invasion by pathogens.
福氏志贺菌已进化出利用细胞内活性效应蛋白改变宿主细胞功能的能力，以克服肠道屏障。检测这些微生物效应蛋白并启动先天免疫反应对于快速激活黏膜防御至关重要。鸟嘌呤核苷酸交换因子H1（GEF-H1）介导肠道侵袭性病原体福氏志贺菌侵袭细胞所需的RhoA激活。令人惊讶的是，GEF-H1是响应志贺菌感染时NF-κB激活所必需的。GEF-H1与NOD1相互作用，并且是H-Ala-D-γGlu-DAP（γTriDAP）依赖RIP2激活NF-κB所必需的。GEF-H1对于志贺菌效应蛋白IpgB2和OspB激活NF-κB至关重要，发现它们以NOD1和RhoA激酶（ROCK）依赖的方式发出信号。我们的结果表明，GEF-H1是细胞防御的关键组成部分，在病原体侵袭细胞期间与NOD1形成细胞内传感系统以检测微生物效应蛋白。
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