RACK1 interacts with filamin-A to regulate plasma membrane levels of the cystic fibrosis transmembrane conductance regulator.
RACK1 interacts with filamin-A to regulate plasma membrane levels of the cystic fibrosis transmembrane conductance regulator.
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DOI：
10.1152/ajpcell.00026.2013
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发表时间：
2013-07
期刊：
影响因子：
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通讯作者：
Laura Smith;P. Litman;E. Kohli;Joseph Amick;R. Page;S. Misra;C. Liedtke
中科院分区：
文献类型：
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作者：
Laura Smith;P. Litman;E. Kohli;Joseph Amick;R. Page;S. Misra;C. Liedtke
囊性纤维化跨膜调节因子（CFTR）是分泌性上皮细胞顶膜中的氯离子通道，其突变是致命的遗传性疾病囊性纤维化的基础。某些 CFTR 突变，包括常见突变 ΔF508-CFTR，会导致顶膜活性 CFTR 水平大大降低。 CFTR 与细胞骨架适配器 filamin-A (FlnA) 和 Na(+)/H(+) 交换调节因子 1 (NHERF1) 之间的直接相互作用稳定 CFTR 在质膜上的表达和定位。活化 C 激酶 1 (RACK1) 的支架蛋白受体还可稳定 CFTR 表面表达；然而，RACK1 并不直接与 CFTR 相互作用，其作用机制尚不清楚。在本研究中，我们报告 RACK1 在体外和 Calu-3 气道上皮细胞系中直接与 FlnA 相互作用。我们将 RACK1 和 FlnA 之间的相互作用映射到 RACK1 的 WD4 和 WD6 重复序列以及 FlnA 大杆结构域的片段（由免疫球蛋白样重复序列 8-15 组成）。 RACK1-FlnA 相互作用的破坏会导致 CFTR 表面水平降低。我们的结果表明，一种新型的 RACK1-FlnA 相互作用是 CFTR 表面定位的重要调节因子。
Mutations in cystic fibrosis transmembrane regulator (CFTR), a chloride channel in the apical membranes of secretory epithelial cells, underlie the fatal genetic disorder cystic fibrosis. Certain CFTR mutations, including the common mutation ΔF508-CFTR, result in greatly decreased levels of active CFTR at the apical membrane. Direct interactions between CFTR and the cytoskeletal adaptors filamin-A (FlnA) and Na(+)/H(+) exchanger regulatory factor 1 (NHERF1) stabilize the expression and localization of CFTR at the plasma membrane. The scaffold protein receptor for activated C kinase 1 (RACK1) also stabilizes CFTR surface expression; however, RACK1 does not interact directly with CFTR and its mechanism of action is unknown. In the present study, we report that RACK1 interacts directly with FlnA in vitro and in a Calu-3 airway epithelial cell line. We mapped the interaction between RACK1 and FlnA to the WD4 and WD6 repeats of RACK1 and to a segment of the large rod domain of FlnA, consisting of immunoglobulin-like repeats 8-15. Disruption of the RACK1-FlnA interaction causes a reduction in CFTR surface levels. Our results suggest that a novel RACK1-FlnA interaction is an important regulator of CFTR surface localization.