Henry Katherine R, Lee Seakwoo, Walker Douglas, Zeitlin Pamela L
Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Physiol Rep. 2015 Jan 27;3(1). doi: 10.14814/phy2.12264. Print 2015 Jan 1.
Cystic fibrosis (CF) is a lethal disease caused by mutations in the chloride channel CFTR gene. The disease is characterized by decreased chloride secretion and unregulated sodium absorption through the epithelial sodium channel (ENaC) in the airway epithelium and other affected organs. We hypothesize that a non-CFTR alternative chloride channel ClCN2 can be activated to negatively regulate ENaC in CF epithelial cell cultures. We identified a novel interaction between ClCN2 and the ENaCγ subunit in CF airway epithelial cells and show that the upregulation of ClCN2 leads to decreased expression of ENaCγ via a K63 ubiquitination mechanism. These regulatory effects of ClCN2 on ENaCγ appear to be dependent on the CBS-1 domain located within the c-terminus of ClCN2, which is necessary for the targeting of ClCN2 to the apical surface. In sum, these results suggest the ability of ClCN2 to negatively regulate sodium absorption through ENaC, supporting its role as a therapeutic target for the treatment of CF.
囊性纤维化（CF）是一种由氯离子通道CFTR基因突变引起的致命疾病。该疾病的特征是气道上皮和其他受影响器官中氯离子分泌减少，以及通过上皮钠通道（ENaC）的钠吸收不受调控。我们假设在CF上皮细胞培养物中，可以激活一种非CFTR替代氯离子通道ClCN2来负向调节ENaC。我们在CF气道上皮细胞中鉴定出ClCN2与ENaCγ亚基之间的一种新型相互作用，并表明ClCN2的上调通过K63泛素化机制导致ENaCγ的表达降低。ClCN2对ENaCγ的这些调节作用似乎依赖于位于ClCN2 c末端的CBS-1结构域，这是ClCN2靶向顶端表面所必需的。总之，这些结果表明ClCN2具有负向调节通过ENaC的钠吸收的能力，支持其作为CF治疗靶点的作用。
