Department of Anatomy, Physiology and Genetics, School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA.
Department of Cell Biology, University of Pittsburgh, School of Medicine, Pittsburgh, PA, 1526, USA.
Sci Rep. 2021 Aug 17;11(1):16645. doi: 10.1038/s41598-021-96141-w.
Cystic fibrosis (CF) occurs as a result of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which lead to misfolding, trafficking defects, and impaired function of the CFTR protein. Splicing factor proline/glutamine-rich (SFPQ) is a multifunctional nuclear RNA-binding protein (RBP) implicated in the regulation of gene expression pathways and intracellular trafficking. Here, we investigated the role of SFPQ in the regulation of the expression and function of F508del-CFTR in CF lung epithelial cells. We find that the expression of SFPQ is reduced in F508del-CFTR CF epithelial cells compared to WT-CFTR control cells. Interestingly, the overexpression of SFPQ in CF cells increases the expression as well as rescues the function of F508del-CFTR. Further, comprehensive transcriptome analyses indicate that SFPQ plays a key role in activating the mutant F508del-CFTR by modulating several cellular signaling pathways. This is the first report on the role of SFPQ in the regulation of expression and function of F508del-CFTR in CF lung disease. Our findings provide new insights into SFPQ-mediated molecular mechanisms and point to possible novel epigenetic therapeutic targets for CF and related pulmonary diseases.
囊性纤维化（CF）是由囊性纤维化跨膜电导调节因子（CFTR）基因突变引起的，导致 CFTR 蛋白错误折叠、运输缺陷和功能受损。剪接因子脯氨酸/谷氨酰胺丰富（SFPQ）是一种多功能核 RNA 结合蛋白（RBP），参与基因表达途径和细胞内运输的调节。在这里，我们研究了 SFPQ 在 CF 肺上皮细胞中对 F508del-CFTR 表达和功能的调节作用。我们发现，与 WT-CFTR 对照细胞相比，F508del-CFTR CF 上皮细胞中 SFPQ 的表达减少。有趣的是，CF 细胞中 SFPQ 的过表达增加了 F508del-CFTR 的表达并挽救了其功能。此外，全面的转录组分析表明，SFPQ 通过调节几个细胞信号通路在激活突变型 F508del-CFTR 中发挥关键作用。这是 SFPQ 在 CF 肺部疾病中调节 F508del-CFTR 表达和功能的作用的首次报道。我们的研究结果为 SFPQ 介导的分子机制提供了新的见解，并为 CF 和相关肺部疾病的可能新的表观遗传治疗靶点指明了方向。
