Zinc Transporter SLC39A7/ZIP7 Promotes Intestinal Epithelial Self-Renewal by Resolving ER Stress

Wakana Ohashi; Shunsuke Kimura; Toshihiko Iwanaga; Yukihiro Furusawa; Tarou Irié; Hironori Izumi; Takashi Watanabe; Atsushi Hijikata; Takafumi Hara; Osamu Ohara; Haruhiko Koseki; Toshiro Sato; Sylvie Robine; Hisashi Mori; Yuichi Hattori; Hiroshi Watarai; Kenji Mishima; Hiroshi Ohno; Koji Hase; Toshiyuki Fukada

doi:10.1371/journal.pgen.1006349

Zinc Transporter SLC39A7/ZIP7 Promotes Intestinal Epithelial Self-Renewal by Resolving ER Stress

PLoS Genet. 2016 Oct 13;12(10):e1006349. doi: 10.1371/journal.pgen.1006349. eCollection 2016 Oct.

Authors

Wakana Ohashi^{1

2}, Shunsuke Kimura³, Toshihiko Iwanaga³, Yukihiro Furusawa^{4

5}, Tarou Irié⁶, Hironori Izumi⁷, Takashi Watanabe⁸, Atsushi Hijikata⁹, Takafumi Hara¹⁰, Osamu Ohara^{8

11}, Haruhiko Koseki¹², Toshiro Sato¹³, Sylvie Robine¹⁴, Hisashi Mori⁷, Yuichi Hattori², Hiroshi Watarai¹⁵, Kenji Mishima⁶, Hiroshi Ohno¹⁶, Koji Hase^{4

5}, Toshiyuki Fukada^{1

6

10}

Affiliations

¹ RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
² Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama, Japan.
³ Laboratory of Histology and Cytology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.
⁴ Division of Biochemistry, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan.
⁵ Division of Mucosal Barriology, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
⁶ Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Shinagawa-ku, Tokyo, Japan.
⁷ Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama, Japan.
⁸ Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
⁹ Nagahama Institute of Bio-Science and Technology, Tamura, Nagahama, Shiga, Japan.
¹⁰ Molecular and Cellular Physiology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro, Tokushima, Japan.
¹¹ Department of Technology Development, Kazusa DNA Research Institute, Kisarazu, Chiba, Japan.
¹² Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
¹³ Department of Gastroenterology, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
¹⁴ Equipe de Morphogenese et Signalisation cellulaires UMR 144 CNRS/Institut Curie, Paris, France.
¹⁵ Division of Stem Cell Cellomics, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
¹⁶ Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.

Abstract

Zinc transporters play a critical role in spatiotemporal regulation of zinc homeostasis. Although disruption of zinc homeostasis has been implicated in disorders such as intestinal inflammation and aberrant epithelial morphology, it is largely unknown which zinc transporters are responsible for the intestinal epithelial homeostasis. Here, we show that Zrt-Irt-like protein (ZIP) transporter ZIP7, which is highly expressed in the intestinal crypt, is essential for intestinal epithelial proliferation. Mice lacking Zip7 in intestinal epithelium triggered endoplasmic reticulum (ER) stress in proliferative progenitor cells, leading to significant cell death of progenitor cells. Zip7 deficiency led to the loss of Olfm4+ intestinal stem cells and the degeneration of post-mitotic Paneth cells, indicating a fundamental requirement for Zip7 in homeostatic intestinal regeneration. Taken together, these findings provide evidence for the importance of ZIP7 in maintenance of intestinal epithelial homeostasis through the regulation of ER function in proliferative progenitor cells and maintenance of intestinal stem cells. Therapeutic targeting of ZIP7 could lead to effective treatment of gastrointestinal disorders.

MeSH terms

Animals
Apoptosis / genetics
Cation Transport Proteins / biosynthesis
Cation Transport Proteins / genetics*
Cell Proliferation / genetics*
Endoplasmic Reticulum / genetics
Endoplasmic Reticulum Stress / genetics*
Epithelial Cells / metabolism
Gastrointestinal Tract / growth & development
Gastrointestinal Tract / metabolism
Gene Knockout Techniques
Homeostasis
Intestinal Mucosa / growth & development
Intestinal Mucosa / metabolism
Mice
Organoids / growth & development
Paneth Cells / metabolism
Stem Cells / metabolism
Zinc / metabolism*

Substances

Cation Transport Proteins
Zip7 protein, mouse
Zinc

Grants and funding

This study was supported by grants from the Japan Society for the Promotion of Science (#25860573 and #15K19319 to WO; #221S0003 to HM; #25293114 and #26116709 to KH, #23592239 to TF), Takeda Science Foundation (KH), Nestlé Nutrition Council Japan Research Grants (TF), the NOVARTIS Foundation for the Promotion of Science (TF), the SENSHIN Medical Research Foundation (TF), Nukada memorial foundation (WO) and the Joint Research Project of the Institute of Medical Science, University of Tokyo (WO). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.