Zinc Transporter SLC39A7/ZIP7 Promotes Intestinal Epithelial Self-Renewal by Resolving ER Stress.
Zinc Transporter SLC39A7/ZIP7 Promotes Intestinal Epithelial Self-Renewal by Resolving ER Stress.
复制标题
DOI：
10.1371/journal.pgen.1006349
复制
发表时间：
2016-10
期刊：
影响因子：
4.5
通讯作者：
Fukada T
中科院分区：
文献类型：
--
作者：
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
锌转运蛋白在锌稳态的时空调控中起着重要作用。虽然锌稳态的破坏与肠道炎症和异常上皮形态等疾病有关，但在很大程度上尚不清楚哪些锌转运蛋白负责肠上皮稳态。在这里，我们表明，Zrt-Irt样蛋白（ZIP）转运蛋白ZIP 7，这是高度表达的肠隐窝，是必不可少的肠上皮细胞增殖。在肠上皮中缺乏Zip 7的小鼠触发增殖祖细胞中的内质网（ER）应激，导致祖细胞的显著细胞死亡。Zip 7缺陷导致Olfm 4+肠干细胞的损失和有丝分裂后潘氏细胞的变性，表明Zip 7在稳态肠再生中的基本要求。综上所述，这些发现提供了ZIP 7通过调节增殖祖细胞中的ER功能和维持肠干细胞来维持肠上皮稳态的重要性的证据。ZIP 7的治疗靶向可能导致胃肠道疾病的有效治疗。肠上皮细胞经历持续的自我更新以维持肠内环境的稳定。鉴于锌通量的失调导致肠道疾病，适当的时空调节锌在细胞内室应该是肠上皮自我更新过程的先决条件。锌转运蛋白如Zrt-Irt样蛋白（ZIPs）是微调细胞内锌通量的关键。然而，特定的锌转运蛋白和肠上皮自我更新之间的联系仍有待阐明。在这里，我们发现ZIP 7在肠隐窝中高度表达。这一发现促使我们进一步分析ZIP 7在肠道稳态中的作用。ZIP 7缺陷极大地增强了增殖祖细胞中的ER应激反应，这诱导了凋亡性细胞死亡。这种异常破坏了上皮细胞的增殖和肠的干性。基于这些观察结果，我们推断ZIP 7依赖性锌转运通过改善ER应激促进肠中上皮细胞的剧烈增殖。
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. Intestinal epithelium undergoes continuous self-renewal to maintain intestinal homeostasis. Given that dysregulation of zinc flux causes intestinal disorders, appropriate spatiotemporal regulation of zinc in the intracellular compartments should be a prerequisite for the intestinal epithelial self-renewal process. Zinc transporters such as Zrt-Irt-like proteins (ZIPs) are essential to fine-tune intracellular zinc flux. However, the link between specific zinc transporter(s) and intestinal epithelial self-renewal remains to be elucidated. Here, we found that ZIP7 is highly expressed in the intestinal crypts. The finding motivated us to further analyze the role of ZIP7 in intestinal homeostasis. ZIP7 deficiency greatly enhanced ER stress response in proliferative progenitor cells, which induced apoptotic cell death. This abnormality disrupted epithelial proliferation and intestinal stemness. Based on these observations, we reason that ZIP7-dependent zinc transport facilitates the vigorous epithelial proliferation in the intestine by ameliorating ER stress.
登录
查看更多内容
DOI：
10.1042/bj20130483
发表时间：
2013-10-15
期刊：
The Biochemical journal
影响因子：
--
作者：
Hogstrand C;Kille P;Ackland ML;Hiscox S;Taylor KM
通讯作者：
Taylor KM
影响因子：
23.9
作者：
Metcalfe, Ciara;Kljavin, Noelyn M.;de Sauvage, Frederic J.
通讯作者：
de Sauvage, Frederic J.
影响因子：
15.8
作者：
Heazlewood CK;Cook MC;Eri R;Price GR;Tauro SB;Taupin D;Thornton DJ;Png CW;Crockford TL;Cornall RJ;Adams R;Kato M;Nelms KA;Hong NA;Florin TH;Goodnow CC;McGuckin MA
通讯作者：
McGuckin MA
DOI：
10.1038/nrm3999
发表时间：
2015-06
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Fuchs Y;Steller H
通讯作者：
Steller H
影响因子：
3
作者：
Andreini, Claudia;Bertini, Ivano;Thornton, Janet M.
通讯作者：
Thornton, Janet M.