The Rab8 GTPase regulates apical protein localization in intestinal cells
The Rab8 GTPase regulates apical protein localization in intestinal cells
复制标题
DOI：
10.1038/nature05929
复制
发表时间：
2007-07-19
期刊：
影响因子：
64.8
通讯作者：
Harada, Akihiro
中科院分区：
文献类型：
--
作者：
Sato, Takashi;Mushiake, Sotaro;Harada, Akihiro
已知许多蛋白质参与极化上皮细胞中蛋白质的顶侧/基底侧转运（1-7）。认为小GTP结合蛋白Rab（8）通过AP 1B复合物介导的途径调节极化肾上皮细胞的基底外侧转运（8，9）。然而，Rab 8（Rab 8A）在体内细胞极性中的作用仍然未知。在这里，我们表明，Rab 8是负责本地化的顶端蛋白在肠上皮细胞。我们发现，顶端肽酶和转运定位于溶酶体在Rab 8缺陷小鼠的小肠。它们在溶酶体中的错误定位和降解导致小肠中营养物质吸收率显著降低，最终导致死亡。超微结构上，还观察到顶端微绒毛缩短，扩大的溶酶体数量增加，以及肠细胞中的微绒毛内含物。显示与Rab 8缺陷小鼠相同表型的一个微绒毛包涵体病患者表达减少量的RAB 8（RAB 8A; NM_005370）。我们的研究结果表明，Rab 8是必要的适当定位的顶端蛋白质和各种营养物质的吸收和消化在小肠。
A number of proteins are known to be involved in apical/basolateral transport of proteins in polarized epithelial cells(1-7). The small GTP-binding protein Rab(8) was thought to regulate basolateral transport in polarized kidney epithelial cells through the AP1B-complex-mediated pathway(8,9). However, the role of Rab8 (Rab8A) in cell polarity in vivo remains unknown. Here we show that Rab8 is responsible for the localization of apical proteins in intestinal epithelial cells. We found that apical peptidases and transporters localized to lysosomes in the small intestine of Rab8-deficient mice. Their mislocalization and degradation in lysosomes led to a marked reduction in the absorption rate of nutrients in the small intestine, and ultimately to death. Ultrastructurally, a shortening of apical microvilli, an increased number of enlarged lysosomes, and microvillus inclusions in the enterocytes were also observed. One microvillus inclusion disease patient who shows an identical phenotype to Rab8-deficient mice expresses a reduced amount of RAB8 (RAB8A; NM_005370). Our results demonstrate that Rab8 is necessary for the proper localization of apical proteins and the absorption and digestion of various nutrients in the small intestine.