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

• Published in: PLoS genetics 2016-10, Vol.12 (10), p.e1006349-e1006349
• Main Authors: Ohashi, Wakana, Kimura, Shunsuke, Iwanaga, Toshihiko, Furusawa, Yukihiro, Irié, Tarou, Izumi, Hironori, Watanabe, Takashi, Hijikata, Atsushi, Hara, Takafumi, Ohara, Osamu, Koseki, Haruhiko, Sato, Toshiro, Robine, Sylvie, Mori, Hisashi, Hattori, Yuichi, Watarai, Hiroshi, Mishima, Kenji, Ohno, Hiroshi, Hase, Koji, Fukada, Toshiyuki
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - genetics; Biology and Life Sciences; Cation Transport Proteins - biosynthesis; Cation Transport Proteins - genetics; Cell Proliferation - genetics; Cellular biology; Cellular signal transduction; Dentistry; Endoplasmic reticulum; Endoplasmic Reticulum - genetics; Endoplasmic Reticulum Stress - genetics; Epithelial cells; Epithelial Cells - metabolism; Gastrointestinal Tract - growth & development; Gastrointestinal Tract - metabolism; Gene expression; Gene Knockout Techniques; Genomics; Histology; Homeostasis; Intestinal Mucosa - growth & development; Intestinal Mucosa - metabolism; Laboratories; Medicine; Medicine and Health Sciences; Mice; Neurosciences; Observations; Organoids - growth & development; Paneth Cells - metabolism; Pathology; Pharmaceutical sciences; Pharmaceuticals; Pharmacy; Physiological aspects; Physiology; R&D; Research & development; Research and Analysis Methods; Rodents; Stem cells; Stem Cells - metabolism; Vaccines; Zinc; Zinc - metabolism; Zinc finger proteins
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1006349

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.