期刊
EBIOMEDICINE
卷 27, 期 -, 页码 304-316出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ebiom.2017.12.025
关键词
ZIP2; CFTR; ENaC; Splicing isoform; Mucus hypersecretion; Cystic fibrosis
资金
- Japan Society for the Promotion Science (JSPS) KAKENHI [JP25460102, JP17H03570, JP15J09420]
- JSPS Program on Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation [S2510]
- Program for Leading Graduate Schools HIGO (Health life science: Interdisciplinary and Glocal Oriented
- MEXT, Japan)
- Grants-in-Aid for Scientific Research [17H03570, 17J11629, 15J09420] Funding Source: KAKEN
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 (Delta C-ZIP2), which lacks the C-terminal domain. Importantly, Delta C-ZIP2 levels correlated inversely with wild-type ZIP2 and intracellular Zn2+ levels. Moreover, the splice switch to Delta C-ZIP2 as well as decreased expression of other ZIPs caused zinc deficiency, which is sufficient for induction of MUC5AC; while Delta C-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. (C) 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
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