PNAS：恢复缺陷蛋白功能可有效治疗囊性纤维化病人

近日，来自美国爱荷华州大学Carver医学院的研究人员研究发现了可以恢复一种缺陷蛋白功能的遗传过程，这种缺陷蛋白是引发病人囊性纤维化的主要原因。相关研究成果刊登在了近期的国际杂志PNAS上。

囊性纤维化是一种由基因突变（产生缺陷蛋白）引发所致并且遗传的疾病，在正常机体中，囊性纤维化跨膜传导调节蛋白（CFTR）扮演着离子转运通道的功能，而且对于细胞盐分和水平衡都至关重要。缺少正常的CFTR离子通道会引发很多问题，包括肺部感染和炎症等。

这项研究中，研究者McCray和其同事发现一种特殊的microRNA名为miR-138可以通过调节一系列基因来控制CFTR的生物合成。miR-138可以引导一系列细胞过程进而增加CFTR的产量。

研究者发现当基因网络被miR-138激活后，不仅仅可以增加突变蛋白质的多少，而且可以可以部分恢复蛋白质的功能。通过研究microRNA网络，研究者们改变了错误折叠的CFTR的命运，使其从被降解的命运改变为作为离子通道的角色。

编译自：Gene network restores CF protein function

doi:10.1073/pnas.1210906109
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A microRNA network regulates expression and biosynthesis of wild-type and ΔF508 mutant cystic fibrosis transmembrane conductance regulator

Shyam Ramachandrana,b, Philip H. Karpc, Peng Jiangc, Lynda S. Ostedgaardc, Amy E. Walza, John T. Fisherd, Shaf Keshavjeee, Kim A. Lennoxf, Ashley M. Jacobif, Scott D. Rosef, Mark A. Behlkef, Michael J. Welshb,c,g,h,1, Yi Xingb,c,i,1, and Paul B. McCray, Jra,b,c,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.