Zinc Deficiency via a Splice Switch in Zinc Importer ZIP2/SLC39A2 Causes Cystic Fibrosis-Associated MUC5AC Hypersecretion in Airway Epithelial Cells.
Zinc Deficiency via a Splice Switch in Zinc Importer ZIP2/SLC39A2 Causes Cystic Fibrosis-Associated MUC5AC Hypersecretion in Airway Epithelial Cells.
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DOI：
10.1016/j.ebiom.2017.12.025
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发表时间：
2018-01
期刊：
影响因子：
11.1
通讯作者：
Shuto T
中科院分区：
文献类型：
--
作者：
Kamei S;Fujikawa H;Nohara H;Ueno-Shuto K;Maruta K;Nakashima R;Kawakami T;Matsumoto C;Sakaguchi Y;Ono T;Suico MA;Boucher RC;Gruenert DC;Takeo T;Nakagata N;Li JD;Kai H;Shuto T
呼吸道粘液分泌过多和液体失衡是囊性纤维化（CF）的重要标志，囊性纤维化是白种人中最常见的缩短寿命的遗传性疾病。气道离子转运蛋白（包括囊性纤维化跨膜传导调节因子（CFTR）和上皮钠通道（ENaC））的表达和/或功能失调已被认为是CF相关粘液分泌过多表型的原因。然而，其他物质和转运蛋白在CF气道发病机制的调节中的作用仍不清楚。在这里，我们确定了CFTR/ENaC表达和细胞内Zn 2+浓度在MUC5AC调节中的新联系，MUC5AC是CF气道中高度表达的主要分泌粘蛋白。CFTR缺陷和ENaC过度活跃的气道上皮细胞特异性地高度表达锌输入子ZIP 2/SLC39A2（Δ C-ZIP 2）的独特的选择性剪接异构体，其缺乏C末端结构域。重要的是，Δ C-ZIP2水平与野生型ZIP2和细胞内Zn2+水平呈负相关。此外，剪接转换为Δ C-ZIP2以及其他ZIPs表达的减少导致锌缺乏，这足以诱导MUC5AC;而Δ C-ZIP2表达本身诱导ENaC表达和功能。因此，我们的研究结果表明，新的剪接开关通过CFTR，ENaC和ZIP 2转运蛋白的新的相互作用而导致CF肺病理学。锌缺乏是CFTR缺陷（CF）和ENaC过度活跃（CF样）气道上皮细胞的共同特征。从WT-ZIP2到Δ C-ZIP2的剪接开关以及其他ZIPs下调导致CF和CF样细胞中的锌缺乏。较低的细胞内Zn 2+水平有助于气道上皮细胞中CF相关MUC5AC的高分泌。锌在CF肺病发病机制中的作用还不清楚。我们利用人CF患者来源的细胞系和原代细胞以及鼠CF模型，并将锌缺乏鉴定为CF模型中的共同特征。CF细胞中的几种锌输入物（ZIP）的下调引起锌缺乏，这足以诱导MUC5AC，MUC5AC是加剧CF发病机制的主要分泌粘蛋白。特别地，清楚地证明了Δ C-ZIP2（一种新的ZIP2剪接异构体）在调节CF相关MUC5AC高分泌中的强贡献。该研究进一步阐明了锌在气道内环境稳定中的重要性。
Airway mucus hyperproduction and fluid imbalance are important hallmarks of cystic fibrosis (CF), the most common life-shortening genetic disorder in Caucasians. Dysregulated expression and/or function of airway ion transporters, including cystic fibrosis transmembrane conductance regulator (CFTR) and epithelial sodium channel (ENaC), have been implicated as causes of CF-associated mucus hypersecretory phenotype. However, the contributory roles of other substances and transporters in the regulation of CF airway pathogenesis remain unelucidated. Here, we identified a novel connection between CFTR/ENaC expression and the intracellular Zn2 + concentration in the regulation of MUC5AC, a major secreted mucin that is highly expressed in CF airway. CFTR-defective and ENaC-hyperactive airway epithelial cells specifically and highly expressed a unique, alternative splice isoform of the zinc importer ZIP2/SLC39A2 (ΔC-ZIP2), which lacks the C-terminal domain. Importantly, ΔC-ZIP2 levels correlated inversely with wild-type ZIP2 and intracellular Zn2 + levels. Moreover, the splice switch to ΔC-ZIP2 as well as decreased expression of other ZIPs caused zinc deficiency, which is sufficient for induction of MUC5AC; while ΔC-ZIP2 expression per se induced ENaC expression and function. Thus, our findings demonstrate that the novel splicing switch contributes to CF lung pathology via the novel interplay of CFTR, ENaC, and ZIP2 transporters. Zinc deficiency is a common feature in both CFTR-defective (CF) and ENaC-hyperactive (CF-like) airway epithelial cells. A splice switch from WT-ZIP2 to ΔC-ZIP2 as well as other ZIPs down-regulation caused zinc deficiency in CF and CF-like cells. Lower intracellular Zn2 + levels contributed to CF-associated MUC5AC hypersecretion in airway epithelial cells. The role of zinc in the pathogenesis of CF lung disease is not well understood. We utilized human CF patient-derived cell lines and primary cells as well as murine CF model, and identified zinc deficiency as a common characteristic in CF models. Down-regulation of several zinc importers (ZIPs) in CF cells caused zinc deficiency, which is sufficient for induction of MUC5AC, a major secreted mucin that exacerbates CF pathogenesis. Especially, strong contribution of ΔC-ZIP2, a novel ZIP2 splice isoform, in the regulation of CF-associated MUC5AC hypersecretion was clearly demonstrated. The study refined the importance of zinc in airway homeostasis.
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影响因子：
64.5
作者：
Cooper TA;Wan L;Dreyfuss G
通讯作者：
Dreyfuss G
影响因子：
64.5
作者：
Duce JA;Tsatsanis A;Cater MA;James SA;Robb E;Wikhe K;Leong SL;Perez K;Johanssen T;Greenough MA;Cho HH;Galatis D;Moir RD;Masters CL;McLean C;Tanzi RE;Cappai R;Barnham KJ;Ciccotosto GD;Rogers JT;Bush AI
通讯作者：
Bush AI
DOI：
10.1152/ajplung.00163.2014
发表时间：
2015-01-01
影响因子：
4.9
作者：
Astrand, Annika B. M.;Hemmerling, Martin;Tarran, Robert
通讯作者：
Tarran, Robert
影响因子：
4.3
作者：
Groneberg, DA;Eynott, PR;Chung, KF
通讯作者：
Chung, KF
DOI：
10.1016/j.jtemb.2013.10.003
发表时间：
2014-01-01
影响因子：
3.5
作者：
Damphousse, Veronic;Mailhot, Marjolaine;Mailhot, Genevieve
通讯作者：
Mailhot, Genevieve