c-Cbl reduces stability of rescued ∆F508-CFTR in human airway epithelial cells: Implications for cystic fibrosis treatment.
c-Cbl reduces stability of rescued ∆F508-CFTR in human airway epithelial cells: Implications for cystic fibrosis treatment.
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DOI：
10.4161/cib.23094
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发表时间：
2013-03-01
影响因子：
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通讯作者：
Swiatecka-Urban, Agnieszka
中科院分区：
文献类型：
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作者：
Cihil, Kristine M;Zimnik, Andrew;Swiatecka-Urban, Agnieszka
CFTR是PKA激活的Cl（-）通道，在液体转运上皮细胞的顶膜中表达。我们先前证明，c-Cbl通过促进CFTR在人气道上皮细胞中的内吞作用和溶酶体降解来降低CFTR在质膜中的稳定性。与囊性纤维化相关的最常见的突变，Phe 508（Phe 508）的缺失，导致CFTR蛋白中的温度敏感性生物合成加工缺陷。已经被低温或化学分子伴侣拯救的成熟的CFNF 508-CFTR作为Cl（-）通道具有部分功能，但是由于改变的成熟后运输而具有降低的质膜稳定性。我们目前的数据表明，c-Cbl控制的成熟后贩运获救的BIF 508-CFTR。c-Cbl的部分缺失增加了质膜相关的成熟CFNF 508-CFTR的稳定性和CFNF 508-CFTR介导的Cl（-）分泌。这些数据表明，纠正成熟后运输的BMP 508-CFTR可能代表一种治疗方法的补充生物合成的救援。由于c-Cbl在CFTR内吞作用中起衔接子和支架蛋白的作用，因此我们提出，干扰c-Cbl介导的CF 508-CFTR的内吞募集可以增加CF 508-CFTR在其生物合成拯救后在质膜中的稳定性。
CFTR is a PKA activated Cl(-) channel expressed in the apical membrane of fluid transporting epithelia. We previously demonstrated that c-Cbl decreases CFTR stability in the plasma membrane by facilitating its endocytosis and lysosomal degradation in human airway epithelium. The most common mutation associated with cystic fibrosis, deletion of Phe508 (∆F508), leads to a temperature sensitive biosynthetic processing defect in the CFTR protein. Mature ∆F508-CFTR that has been rescued by low temperature or chemical chaperones is partially functional as a Cl(-) channel but has decreased plasma membrane stability due to altered post-maturational trafficking. Our present data demonstrate that c-Cbl controls the post-maturational trafficking of rescued ∆F508-CFTR. Partial depletion of c-Cbl increased stability of the plasma membrane associated mature ∆F508-CFTR and the ∆F508-CFTR mediated Cl(-) secretion. These data indicate that correcting the post-maturational trafficking of ∆F508-CFTR may represent a therapeutic approach complementary to the biosynthetic rescue. Because c-Cbl functions as an adaptor and scaffolding protein during CFTR endocytosis, we propose that interfering with the c-Cbl mediated endocytic recruitment of ∆F508-CFTR may increase stability of ∆508-CFTR in the plasma membrane after its biosynthetic rescue.