Journal Article

The Rab8 GTPase regulates apical protein localization in intestinal cells

Mushiake, Sotaro, Miki, Kazunori, Kato, Yukio, Takeda, Naoki, Harada, Reiko, Ozono, Keiichi, Sato, Miyuki, Tsuji, Akira, Harada, Akihiro, Sato, Takashi, Sato, Ken, Kubo, Yoshiyuki

2007

Overview

Rab8 is a small GTP-binding protein thought to regulate basolateral transport in vitro . In this paper, Rab8 conditional knockout mice are used to show that Rab8 plays an important part in vivo in the maintenance of the apical surface of intestinal cells; the mice eventually starve owing to poor absorption of food. A number of proteins are known to be involved in apical/basolateral transport of proteins in polarized epithelial cells 1 , 2 , 3 , 4 , 5 , 6 , 7 . The small GTP-binding protein Rab8 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.

• Publisher: Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
• Subject: Absorption / Animals / Binding sites / Biological and medical sciences / Cell physiology / Cell Polarity / Cellular biology / Cytoplasm - metabolism / Epithelial cells / Epithelial Cells - cytology / Epithelial Cells - enzymology / Epithelial Cells - metabolism / Epithelial Cells - pathology / Fundamental and applied biological sciences. Psychology / Guanosine triphosphatase / Humanities and Social Sciences / Humans / Inclusions / Intestinal Absorption / Intestines / Intestines - cytology / Intestines - enzymology / Intestines - metabolism / Intestines - pathology / Kidneys / letter / Localization / Lysosomes / Lysosomes - metabolism / Mice / Mice, Knockout / Microvilli - enzymology / Microvilli - metabolism / Microvilli - pathology / Miscellaneous / Molecular and cellular biology / multidisciplinary / Nutrients / Peptide Hydrolases - metabolism / Polarity (Biology) / Position (location) / Protein Transport / Proteins / rab GTP-Binding Proteins - deficiency / rab GTP-Binding Proteins - genetics / rab GTP-Binding Proteins - metabolism / Rodents / Science / Science (multidisciplinary)