Department of Pediatrics, Interdisciplinary Program in Genetics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Proc Natl Acad Sci U S A. 2012 Aug 14;109(33):13362-7. doi: 10.1073/pnas.1210906109. Epub 2012 Aug 1.
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, ΔF508, causes protein misfolding, protein degradation, and cystic fibrosis. Remarkably, manipulating the miR-138 regulatory network also improved biosynthesis of CFTR-ΔF508 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.
生产功能性蛋白质需要多个步骤，包括基因转录和翻译后加工。microRNAs（miRNAs）可以调节这些过程的各个阶段。尽管囊性纤维化跨膜电导调节因子（CFTR）通道对上皮阴离子转运很重要，但它的表达如何调节仍不确定。我们发现 miRNA-138 通过与转录调节蛋白 SIN3A 的相互作用来调节 CFTR 的表达。用 miR-138 模拟物处理气道上皮细胞可增加 CFTR mRNA 的表达，并且独立于 mRNA 水平的升高增强 CFTR 的丰度和跨上皮 Cl(-)通透性。miR-138 反义 miRNA 则具有相反的效果。重要的是，miR-138 改变了与 CFTR 相关的许多编码蛋白的基因表达，并可能影响其生物合成。最常见的 CFTR 突变，ΔF508，导致蛋白质错误折叠、蛋白质降解和囊性纤维化。值得注意的是，操纵 miR-138 调节网络也改善了 CFTR-ΔF508 的生物合成，并恢复了囊性纤维化气道上皮细胞的 Cl(-)转运。这个 miRNA 调节网络将基因表达从染色体导向细胞膜，表明单个 miRNA 可以比以前认识到的更广泛地控制细胞过程。这一发现还为恢复受最常见囊性纤维化突变影响的细胞的 CFTR 功能提供了治疗途径。
