EPEC effector EspF promotes Crumbs3 endocytosis and disrupts epithelial cell polarity.
EPEC effector EspF promotes Crumbs3 endocytosis and disrupts epithelial cell polarity.
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DOI：
10.1111/cmi.12757
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发表时间：
2017-11
影响因子：
3.4
通讯作者：
Hecht GA
中科院分区：
文献类型：
--
作者：
Tapia R;Kralicek SE;Hecht GA
肠致病性大肠杆菌（EPEC）使用第三型分泌系统将效应蛋白注入宿主肠上皮细胞引起腹泻。EPEC感染使基底外侧蛋白β1-整合素和Na+/K+ ATP酶重新分布到宿主细胞的顶膜。Crumbs（Crb）极性复合物（Crb 3/Pals 1/Patj）是上皮细胞极化和紧密连接（TJ）组装所必需的。在这里，我们证明，EPEC取代Crb 3和Pals 1从顶膜的细胞质培养的肠上皮细胞和感染小鼠的结肠细胞。体外研究表明，EspF，而不是地图改变Crb 3，而这两个效应器调节Pals 1。EspF在包囊形态发生测定中干扰极性形成，并诱导Na+/K+ ATP酶的内吞作用和顶端再分布。EspF与分选连接蛋白9（SNX 9）结合，导致宿主细胞中的膜重塑。感染ΔespF/pespFD 3（一种消除EspF与SNX 9结合的突变株）或抑制发动蛋白可减弱EPEC引起的Crb 3内吞作用。此外，感染ΔespF/pespFD 3对Na+/K+ ATP酶内吞作用没有影响。这些数据支持EPEC以EspF依赖性方式扰乱顶部-基底极性的假设，这将通过破坏TJ并改变参与离子和溶质吸收的膜转运蛋白的关键定位而导致EPEC相关腹泻。
Enteropathogenic Escherichia coli (EPEC) uses a type three secretion system to inject effector proteins into host intestinal epithelial cells causing diarrhea. EPEC infection redistributes basolateral proteins β1-integrin and Na+/K+ ATPase to the apical membrane of host cells. The Crumbs (Crb) polarity complex (Crb3/Pals1/Patj) is essential for epithelial cell polarization and tight junction (TJ) assembly. Here we demonstrate that EPEC displaces Crb3 and Pals1 from the apical membrane to the cytoplasm of cultured intestinal epithelial cells and colonocytes of infected mice. In vitro studies show that EspF, but not Map alters Crb3, while both effectors modulate Pals1. EspF perturbs polarity formation in cyst morphogenesis assays and induces endocytosis and apical redistribution of Na+/K+ ATPase. EspF binds to sorting nexin 9 (SNX9) causing membrane remodeling in host cells. Infection with ΔespF/pespFD3, a mutant strain that ablates EspF binding to SNX9, or inhibition of dynamin attenuates Crb3 endocytosis caused by EPEC. In addition, infection with ΔespF/pespFD3 has no impact on Na+/K+ ATPase endocytosis. These data support the hypothesis that EPEC perturbs apical-basal polarity in an EspF-dependent manner, which would contribute to EPEC-associated diarrhea by disruption of TJ and altering the crucial positioning of membrane transporters involved in the absorption of ions and solutes.
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