Department of GI surgery, Shanghai Tenth People's Hospital Affiliated with Tongji University, 301 Yanchang Road, Shanghai 200072, China.
The University of Chicago, Ben May Department for Cancer Research, Chicago, Illinois 60637, USA.
Nat Commun. 2017 May 25;8:15375. doi: 10.1038/ncomms15375.
In the intestinal epithelium, the aberrant regulation of cell/cell junctions leads to intestinal barrier defects, which may promote the onset and enhance the severity of inflammatory bowel disease (IBD). However, it remains unclear how the coordinated behaviour of cytoskeletal network may contribute to cell junctional dynamics. In this report, we identified ACF7, a crosslinker of microtubules and F-actin, as an essential player in this process. Loss of ACF7 leads to aberrant microtubule organization, tight junction stabilization and impaired wound closure in vitro. With the mouse genetics approach, we show that ablation of ACF7 inhibits intestinal wound healing and greatly increases susceptibility to experimental colitis in mice. ACF7 level is also correlated with development and progression of ulcerative colitis (UC) in human patients. Together, our results reveal an important molecular mechanism whereby coordinated cytoskeletal dynamics contributes to cell adhesion regulation during intestinal wound repair and the development of IBD.
在肠道上皮细胞中,细胞/细胞连接的异常调节导致肠道屏障缺陷,这可能促进炎症性肠病(IBD)的发生并加重其严重程度。然而,细胞骨架网络的协调行为如何促进细胞连接动力学尚不清楚。在本报告中,我们鉴定了 ACF7,一种微管和 F-肌动蛋白的交联物,作为该过程的必需因子。ACF7 的缺失导致微管组织异常、紧密连接稳定和体外伤口闭合受损。通过小鼠遗传学方法,我们发现 ACF7 的缺失抑制了肠道伤口愈合,并大大增加了小鼠实验性结肠炎的易感性。ACF7 的水平也与人类溃疡性结肠炎(UC)的发展和进展相关。总之,我们的结果揭示了一个重要的分子机制,即协调的细胞骨架动力学有助于肠道伤口修复过程中细胞黏附的调节以及 IBD 的发展。