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

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

Research output: Contribution to journal › Article › peer-review

70 Citations (Scopus)

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.

Original language	English
Article number	e1006349
Journal	PLoS Genetics
Volume	12
Issue number	10
DOIs	https://doi.org/10.1371/journal.pgen.1006349
Publication status	Published - 2016 Oct

ASJC Scopus subject areas

Ecology, Evolution, Behavior and Systematics
Molecular Biology
Genetics
Genetics(clinical)
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Ohashi, W., Kimura, S., Iwanaga, T., Furusawa, Y., Irié, T., Izumi, H., Watanabe, T., Hijikata, A., Hara, T., Ohara, O., Koseki, H., Sato, T., Robine, S., Mori, H., Hattori, Y., Watarai, H., Mishima, K., Ohno, H., Hase, K., & Fukada, T. (2016). Zinc Transporter SLC39A7/ZIP7 Promotes Intestinal Epithelial Self-Renewal by Resolving ER Stress. PLoS Genetics, 12(10), Article e1006349. https://doi.org/10.1371/journal.pgen.1006349

Ohashi, W, Kimura, S, Iwanaga, T, Furusawa, Y, Irié, T, Izumi, H, Watanabe, T, Hijikata, A, Hara, T, Ohara, O, Koseki, H, Sato, T, Robine, S, Mori, H, Hattori, Y, Watarai, H, Mishima, K, Ohno, H, Hase, K & Fukada, T 2016, 'Zinc Transporter SLC39A7/ZIP7 Promotes Intestinal Epithelial Self-Renewal by Resolving ER Stress', PLoS Genetics, vol. 12, no. 10, e1006349. https://doi.org/10.1371/journal.pgen.1006349

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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.",

author = "Wakana Ohashi and Shunsuke Kimura and Toshihiko Iwanaga and Yukihiro Furusawa and Tarou Iri{\'e} and Hironori Izumi and Takashi Watanabe and Atsushi Hijikata and Takafumi Hara and Osamu Ohara and Haruhiko Koseki and Toshiro Sato and Sylvie Robine and Hisashi Mori and Yuichi Hattori and Hiroshi Watarai and Kenji Mishima and Hiroshi Ohno and Koji Hase and Toshiyuki Fukada",

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AU - Iwanaga, Toshihiko

AU - Furusawa, Yukihiro

AU - Irié, Tarou

AU - Izumi, Hironori

AU - Watanabe, Takashi

AU - Hijikata, Atsushi

AU - Hara, Takafumi

AU - Ohara, Osamu

AU - Koseki, Haruhiko

AU - Sato, Toshiro

AU - Robine, Sylvie

AU - Mori, Hisashi

AU - Hattori, Yuichi

AU - Watarai, Hiroshi

AU - Mishima, Kenji

AU - Ohno, Hiroshi

AU - Hase, Koji

AU - Fukada, Toshiyuki

PY - 2016/10

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N2 - 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.

AB - 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.

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

Abstract

ASJC Scopus subject areas

UN SDGs

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