期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 109, 期 33, 页码 13362-13367出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1210906109
关键词
ATP-binding cassette transporter; epithelial ion transport; protein biosynthesis
资金
- National Institutes of Health [R21 HL-91808, P01 HL-51670, P30 DK-054759, P01 HL-091842]
- Roy J. Carver Charitable Trust
- Cystic Fibrosis Foundation Research Development Program
- Center for Gene Therapy for Cystic Fibrosis (National Institutes of Health) [P30 DK-54759]
- Cystic Fibrosis Foundation
Production of functional proteins requires multiple steps, including gene transcription and posttranslational processing. MicroRNAs (miRNAs) can regulate individual stages of these processes. Despite the importance of the cystic fibrosis transmembrane conductance regulator (CFTR) channel for epithelial anion transport, how its expression is regulated remains uncertain. We discovered that miRNA-138 regulates CFTR expression through its interactions with the transcriptional regulatory protein SIN3A. Treating airway epithelia with an miR-138 mimic increased CFTR mRNA and also enhanced CFTR abundance and transepithelial Cl- permeability independent of elevated mRNA levels. An miR-138 anti-miR had the opposite effects. Importantly, miR-138 altered the expression of many genes encoding proteins that associate with CFTR and may influence its biosynthesis. The most common CFTR mutation, Delta F508, causes protein misfolding, protein degradation, and cystic fibrosis. Remarkably, manipulating the miR-138 regulatory network also improved biosynthesis of CFTR-Delta F508 and restored Cl- transport to cystic fibrosis airway epithelia. This miRNA-regulated network directs gene expression from the chromosome to the cell membrane, indicating that an individual miRNA can control a cellular process more broadly than recognized previously. This discovery also provides therapeutic avenues for restoring CFTR function to cells affected by the most common cystic fibrosis mutation.
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