Zinc Deficiency via a Splice Switch in Zinc Importer ZIP2/SLC39A2 Causes Cystic Fibrosis-Associated MUC5AC Hypersecretion in Airway Epithelial Cells
| Autor: | Jian Dong Li, Naomi Nakagata, Chizuru Matsumoto, Keiko Ueno-Shuto, Ryunosuke Nakashima, Kasumi Maruta, Haruka Fujikawa, Hirofumi Nohara, Toru Takeo, Tomomi Ono, Hirofumi Kai, Richard C. Boucher, Shunsuke Kamei, Tsuyoshi Shuto, Taisei Kawakami, Mary Ann Suico, Dieter C. Gruenert, Yuki Sakaguchi |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Epithelial sodium channel Cystic Fibrosis RNA Splicing Respiratory System ENaC lcsh:Medicine Cystic Fibrosis Transmembrane Conductance Regulator Down-Regulation Mucin 5AC Cystic fibrosis General Biochemistry Genetics and Molecular Biology Cell Line 03 medical and health sciences medicine Animals CFTR Epithelial Sodium Channels Cation Transport Proteins lcsh:R5-920 biology Chemistry lcsh:R Mucin ZIP2 Splicing isoform Epithelial Cells General Medicine respiratory system medicine.disease Phenotype Mucus Cystic fibrosis transmembrane conductance regulator Cell biology Up-Regulation Mice Inbred C57BL Zinc 030104 developmental biology Mutation Zinc deficiency biology.protein lcsh:Medicine (General) Intracellular Research Paper Mucus hypersecretion |
| Zdroj: | EBioMedicine EBioMedicine, Vol 27, Iss C, Pp 304-316 (2018) |
| DOI: | 10.17615/wrna-p049 |
| Popis: | 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. Highlights • 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. |
| Databáze: | OpenAIRE |
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