The Rab8 GTPase regulates apical protein localization in intestinal cells.
A number of proteins are known to be involved in apical/basolateral transport of proteins in polarized epithelial cells. The small GTP-binding protein Rab8 was thought to regulate basolateral transport in polarized kidney epithelial cells through the AP1B-complex-mediated pathway. 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.
Sato
Takashi
T
Laboratory of Molecular Traffic, Department of Molecular and Cellullar Biology, Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan.
Mushiake
Sotaro
S
Kato
Yukio
Y
Sato
Ken
K
Sato
Miyuki
M
Takeda
Naoki
N
Ozono
Keiichi
K
Miki
Kazunori
K
Kubo
Yoshiyuki
Y
Tsuji
Akira
A
Harada
Reiko
R
Harada
Akihiro
A
D000818:Animals; D016764:Cell Polarity; D003593:Cytoplasm / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000166:cytology* / Q000201:enzymology / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008871:Microvilli / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D010447:Peptide Hydrolases / Q000378:metabolism; D021381:Protein Transport; D020691:rab GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
C521976:Rab8 protein, mouse; D010447:Peptide Hydrolases; C082377:RAB8A protein, human; D020691:rab GTP-Binding Proteins