BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, 1749-016 Lisbon, Portugal.
Department of Physiology, University of Regensburg, 93053 Regensburg, Germany.
Cells. 2020 Jul 2;9(7):1607. doi: 10.3390/cells9071607.
Cystic Fibrosis (CF) is caused by >2000 mutations in the CF transmembrane conductance regulator (CFTR) gene, but one mutation-F508del-occurs in ~80% of patients worldwide. Besides its main function as an anion channel, the CFTR protein has been implicated in epithelial differentiation, tissue regeneration, and, when dysfunctional, cancer. However, the mechanisms that regulate such relationships are not fully elucidated. Krüppel-like factors (KLFs) are a family of transcription factors (TFs) playing central roles in development, stem cell differentiation, and proliferation. Herein, we hypothesized that these TFs might have an impact on CFTR expression and function, being its missing link to differentiation. Our results indicate that KLF4 (but not KLF2 nor KLF5) is upregulated in CF vs. non-CF cells and that it negatively regulates wt-CFTR expression and function. Of note, F508del-CFTR expressing cells are insensitive to KLF4 modulation. Next, we investigated which KLF4-related pathways have an effect on CFTR. Our data also show that KLF4 modulates wt-CFTR (but not F508del-CFTR) via both the serine/threonine kinase AKT1 (AKT) and glycogen synthase kinase 3 beta (GSK3β) signaling. While AKT acts positively, GSK3β is a negative regulator of CFTR. This crosstalk between wt-CFTR and KLF4 via AKT/ GSK3β signaling, which is disrupted in CF, constitutes a novel mechanism linking CFTR to the epithelial differentiation.
囊性纤维化（CF）是由 CF 跨膜电导调节因子（CFTR）基因中的>2000 种突变引起的，但一种突变-F508del-在全球约 80%的患者中发生。除了其作为阴离子通道的主要功能外，CFTR 蛋白还与上皮细胞分化、组织再生有关，并且在功能失调时与癌症有关。然而，调节这些关系的机制尚未完全阐明。Krüppel 样因子（KLFs）是一类转录因子（TFs），在发育、干细胞分化和增殖中发挥核心作用。在此，我们假设这些 TF 可能对 CFTR 的表达和功能有影响，是其分化的缺失环节。我们的结果表明，CF 与非 CF 细胞相比，KLF4（而非 KLF2 或 KLF5）上调，并且它负调节 wt-CFTR 的表达和功能。值得注意的是，表达 F508del-CFTR 的细胞对 KLF4 调节不敏感。接下来，我们研究了哪些 KLF4 相关途径对 CFTR 有影响。我们的数据还表明，KLF4 通过丝氨酸/苏氨酸激酶 AKT1（AKT）和糖原合成酶激酶 3β（GSK3β）信号调节 wt-CFTR（而非 F508del-CFTR）。虽然 AKT 起积极作用，但 GSK3β 是 CFTR 的负调节剂。wt-CFTR 与 KLF4 之间通过 AKT/GSK3β 信号的这种串扰，在 CF 中被破坏，构成了将 CFTR 与上皮细胞分化联系起来的新机制。
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