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

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

doi:10.1371/journal.pgen.1006349

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.

Highlights

The intestinal epithelium, which renews every 3–5 days, is one of the most rapidly self-renewing tissues in adult mammals [1]
We found that ZIP7 is highly expressed in the intestinal crypts
We reason that ZIP7-dependent zinc transport facilitates the vigorous epithelial proliferation in the intestine by ameliorating endoplasmic reticulum (ER) stress

Summary

Introduction

The intestinal epithelium, which renews every 3–5 days, is one of the most rapidly self-renewing tissues in adult mammals [1]. Homeostasis of the intestinal epithelium requires a fine balance between cell proliferation, migration, differentiation, and death [1]. Intestinal stem cells are characterized by expression of specific markers such as Lgr, Olfm, and Ascl2 [2,3,4,5]. They divide to form transit-amplifying (TA) cells, which are localized to the lower part of the crypt [2]. TA cells divide continuously, and the daughter cells differentiate into absorptive enterocytes and secretory cell lineages: goblet cells, enteroendocrine cells, and Paneth cells

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