Defective CFTR apical endocytosis and enterocyte brush border in myosin VI-deficient mice
Defective CFTR apical endocytosis and enterocyte brush border in myosin VI-deficient mice
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DOI：
10.1111/j.1600-0854.2007.00587.x
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发表时间：
2007-08-01
期刊：
影响因子：
4.5
通讯作者：
Apodaca, Gerard
中科院分区：
文献类型：
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作者：
Ameen, Nadia;Apodaca, Gerard
在极化的上皮细胞中，如内耳、肾脏和肠道中，肌球蛋白VI已经定位于微绒毛间域，在那里它被认为调节依赖于笼蛋白的内吞作用；然而，肌球蛋白VI在顶端内吞作用中的直接作用尚未被显示。我们研究了囊性纤维化跨膜电导调节剂(CFTR)在肌球蛋白VI基因缺陷的Snell‘s Waltzer Myo6((SV/SV))小鼠的顶膜分布和内吞作用。共聚焦显微镜和细胞表面生物素化实验证实，Myo6((SV/SV))小鼠肠道表面CFTR水平明显高于杂合子对照组，根尖质膜CFTR内化水平低于杂合子对照组。在Myo6((SV/SV))小鼠中，用GMP激活的热稳定肠毒素处理分离的空肠后，观察到CFTR介导的液体分泌增加，这与CFTR内吞和细胞表面积聚的缺陷一致。这些数据表明，肌球蛋白VI调节顶端内吞作用，并可能是CFTR功能和CFTR相关肠道分泌性腹泻的重要生理调节器。
In polarized epithelial cells such as those that line the inner ear, kidney and gut, myosin VI has been localized to the intermicrovillar domains where it is proposed to regulate clathrin-dependent endocytosis; however, a direct role for myosin VI in apical endocytosis has not been shown. We examined the apical membrane distribution and endocytosis of cystic fibrosis transmembrane conductance regulator (CFTR) in myosin VI-deficient Snell's Waltzer Myo6((sv/sv)) mice. Confocal microscopy and cell-surface biotinylation confirmed that surface levels of CFTR in the intestine of Myo6((sv/sv))) mice were markedly higher, and CFTR internalization from the apical plasma membrane was reduced compared with heterozygous controls. Consistent with a defect in CFTR endocytosis and accumulation at the cell surface, exaggerated CFTR-mediated fluid secretion was observed in Myo6((sv/sv)) mice following treatment of isolated jejunum with the cyclic GMP-activated heat stable enterotoxin. These data establish that myosin VI modulates apical endocytosis and may be an important physiological modulator of CFTR function and CFTR-associated secretory diarrhea in the gut.