美国基因泰克公司Vishva M. Dixit小组在研究中取得进展。他们的论文发现了肠致病菌逃避ROCK驱动的上皮细胞挤压。该研究于2025年10月22日发表于国际一流学术期刊《自然》杂志上。
在这里，课题组研究人员发现大肠杆菌泛素连接酶NleL是肠上皮细胞（IEC）外移离子的抑制剂，靶向caspase-4、ROCK1和ROCK2进行蛋白酶体降解。体外培养的IECs中Rock1和Rock2基因缺失可减少炎症小体诱导的IEC挤出。
此外，Rock1和Rock2缺失IEC的小鼠在抑制结肠中啮齿柠檬酸杆菌数量方面的效果不如野生型小鼠。值得注意的是，NleL缺陷的啮齿鼠比野生型啮齿鼠触发了更多的IEC外泌，导致感染小鼠结肠定植减少。他们的工作突出了宿主-病原体军备竞赛的焦点是宿主上皮屏障的动态调节。
据了解，多种病原体编码的毒力因子使细胞凋亡、焦亡或坏死等宿主细胞死亡程序失效。在肠道中，受感染细胞进入腔内进行清除提供了额外的宿主防御层，但目前尚不清楚针对细胞骨架变化的毒力机制。
附：英文原文
Title: Enteropathogenic bacteria evade ROCK-driven epithelial cell extrusion
Author: Luchetti, Giovanni, Miner, Marin V., Peterson, Rachael M., Scott, William P., Krishnamoorthy, Praveen, Kofoed, Eric M., Jimenez, Angel G., Zhang, Hua, Tan, Man Wah, Reja, Rohit, Cheung, Tommy K., Skippington, Elizabeth, Liang, Yuxin, Rose, Christopher M., Kayagaki, Nobuhiko, Newton, Kim, Rauch, Isabella, Dixit, Vishva M.
Issue&Volume: 2025-10-22
Abstract: Diverse pathogen-encoded virulence factors disable apoptosis, pyroptosis or necroptosis, the host cell death programs that remove infected cells1. In the intestine, the extrusion of infected cells into the lumen for elimination provides an additional layer of host defence, but no virulence mechanisms that target the cytoskeletal changes required are known2. Here we show that the Escherichia coli ubiquitin ligase NleL is an inhibitor of intestinal epithelial cell (IEC) extrusion, targeting caspase-4, ROCK1 and ROCK2 for proteasomal degradation. Genetic deletion of Rock1 and Rock2 from cultured IECs diminished inflammasome-induced IEC extrusion. Moreover, mice with Rock1- and Rock2-deficient IECs were less effective than wild-type mice at constraining the numbers of Citrobacter rodentium in the colon. Notably, NleL-deficient C. rodentium triggered more IEC extrusion than did wild-type C. rodentium, resulting in diminished colonization of the colon in infected mice. Our work highlights a host–pathogen arms race focused on dynamic regulation of the host epithelial barrier.
DOI: 10.1038/s41586-025-09645-0