1. Laboratory of Molecular Traffic, Department of Molecular and Cellullar Biology, Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan
2. Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
3. Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa 920-1192, Japan
4. Division of Transgenic Technology, Center for Animal Resources and Development (CARD), IRDA, Kumamoto University, Kumamoto 860-0811, Japan
5. Department of Pediatrics, Itami Municipal Hospital, Hyogo 664-8540, Japan

Correspondence to: Akihiro Harada¹ Correspondence and requests for materials should be addressed to A.H. (Email: aharada@showa.gunma-u.ac.jp).

Abstract

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.

1. Laboratory of Molecular Traffic, Department of Molecular and Cellullar Biology, Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan
2. Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
3. Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa 920-1192, Japan
4. Division of Transgenic Technology, Center for Animal Resources and Development (CARD), IRDA, Kumamoto University, Kumamoto 860-0811, Japan
5. Department of Pediatrics, Itami Municipal Hospital, Hyogo 664-8540, Japan

Correspondence to: Akihiro Harada¹ Correspondence and requests for materials should be addressed to A.H. (Email: aharada@showa.gunma-u.ac.jp).

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