Arsenic Promotes Ubiquitinylation and Lysosomal Degradation of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Chloride Channels in Human Airway Epithelial Cells
Arsenic Promotes Ubiquitinylation and Lysosomal Degradation of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Chloride Channels in Human Airway Epithelial Cells
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DOI：
10.1074/jbc.m111.338855
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发表时间：
2012-05-18
影响因子：
4.8
通讯作者：
Stanton, Bruce A.
中科院分区：
文献类型：
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作者：
Bomberger, Jennifer M.;Coutermarsh, Bonita A.;Stanton, Bruce A.
砷暴露会显著增加呼吸道细菌感染，降低先天免疫系统消除细菌感染的能力。最近，我们在鳉鱼（一种环境模式生物）的鳃中观察到，砷暴露诱导囊性纤维化跨膜传导调节剂（CFTR）的泛素化和降解，CFTR是一种氯离子通道，对人类呼吸道病原体的粘膜纤毛清除至关重要。因此，在本研究中，我们验证了低剂量砷暴露会降低人气道上皮细胞中CFTR的丰度和功能的假设。砷诱导多泛素化CFTR呈时间和剂量依赖性增加，导致其溶酶体降解，并减少CFTR介导的氯化物分泌。虽然砷对USP10的丰度和活性没有影响，但一种去泛素化酶，sirna介导的E3泛素连接酶c-Cbl的敲除，消除了砷刺激的CFTR降解。砷通过增加磷酸化的c-Cbl，从而增加其与CFTR的相互作用，以及随后的CFTR泛素化，从而增强了CFTR的降解。由于流行病学研究表明砷会增加呼吸道感染的发生率，本研究提示这种影响的一种潜在机制涉及砷诱导的CFTR泛素化和降解，从而减少氯化物分泌和气道表面液体体积，从而减少呼吸道病原体的粘膜纤毛清除。
Arsenic exposure significantly increases respiratory bacterial infections and reduces the ability of the innate immune system to eliminate bacterial infections. Recently, we observed in the gill of killifish, an environmental model organism, that arsenic exposure induced the ubiquitinylation and degradation of cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel that is essential for the mucociliary clearance of respiratory pathogens in humans. Accordingly, in this study, we tested the hypothesis that low dose arsenic exposure reduces the abundance and function of CFTR in human airway epithelial cells. Arsenic induced a time- and dose-dependent increase in multiubiquitinylated CFTR, which led to its lysosomal degradation, and a decrease in CFTR-mediated chloride secretion. Although arsenic had no effect on the abundance or activity of USP10, a deubiquitinylating enzyme, siRNA-mediated knock-down of c-Cbl, an E3 ubiquitin ligase, abolished the arsenic-stimulated degradation of CFTR. Arsenic enhanced the degradation of CFTR by increasing phosphorylated c-Cbl, which increased its interaction with CFTR, and subsequent ubiquitinylation of CFTR. Because epidemiological studies have shown that arsenic increases the incidence of respiratory infections, this study suggests that one potential mechanism of this effect involves arsenic-induced ubiquitinylation and degradation of CFTR, which decreases chloride secretion and airway surface liquid volume, effects that would be proposed to reduce mucociliary clearance of respiratory pathogens.