Marsico Lung Institute, University of North Carolina, Chapel Hill, NC, USA.
Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle-upon-Tyne, UK.
Sci Rep. 2019 Sep 20;9(1):13655. doi: 10.1038/s41598-019-49544-9.
Chronic obstructive pulmonary disease (COPD), which is most commonly caused by cigarette smoke (CS) exposure, is the third leading cause of death worldwide. The cystic fibrosis transmembrane conductance regulator (CFTR) is an apical membrane anion channel that is widely expressed in epithelia throughout the body. In the airways, CFTR plays an important role in fluid homeostasis and helps flush mucus and inhaled pathogens/toxicants out of the lung. Inhibition of CFTR leads to mucus stasis and severe airway disease. CS exposure also inhibits CFTR, leading to the decreased anion secretion/hydration seen in COPD patients. However, the underlying mechanism is poorly understood. Here, we report that CS causes CFTR to be internalized in a clathrin/dynamin-dependent fashion. This internalization is followed by retrograde trafficking of CFTR to the endoplasmic reticulum. Although this internalization pathway has been described for bacterial toxins and cargo machinery, it has never been reported for mammalian ion channels. Furthermore, the rapid internalization of CFTR is dependent on CFTR dephosphorylation by calcineurin, a protein phosphatase that is upregulated by CS. These results provide new insights into the mechanism of CFTR internalization, and may help in the development of new therapies for CFTR correction and lung rehydration in patients with debilitating airway diseases such as COPD.
慢性阻塞性肺疾病（COPD），最常见的病因是香烟烟雾（CS）暴露，是全球范围内的第三大致死原因。囊性纤维化跨膜电导调节因子（CFTR）是一种顶端膜阴离子通道，在全身上皮细胞中广泛表达。在气道中，CFTR 在液体动态平衡中发挥重要作用，有助于将黏液和吸入的病原体/毒物从肺部冲洗出去。CFTR 的抑制导致黏液停滞和严重的气道疾病。CS 暴露也抑制 CFTR，导致 COPD 患者中阴离子分泌/水合作用减少。然而，其潜在机制尚不清楚。在这里，我们报告 CS 以网格蛋白/动力蛋白依赖的方式导致 CFTR 内化。这种内化之后是 CFTR 逆行转运到内质网。尽管这个内化途径已经在细菌毒素和货物机制中被描述过，但在哺乳动物离子通道中从未有过报道。此外，CFTR 的快速内化依赖于 CFTR 由钙调神经磷酸酶去磷酸化，钙调神经磷酸酶是一种被 CS 上调的蛋白磷酸酶。这些结果为 CFTR 内化的机制提供了新的见解，并可能有助于开发新的治疗方法，以纠正 CFTR 并使患有 COPD 等严重气道疾病的患者的肺部再水化。
