Rescue of ΔF508-CFTR Trafficking via a GRASP-Dependent Unconventional Secretion Pathway
Rescue of ΔF508-CFTR Trafficking via a GRASP-Dependent Unconventional Secretion Pathway
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DOI：
10.1016/j.cell.2011.07.021
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发表时间：
2011-09-02
期刊：
影响因子：
64.5
通讯作者：
Lee, Min Goo
中科院分区：
文献类型：
--
作者：
Gee, Heon Yung;Noh, Shin Hye;Lee, Min Goo
最常见的致病突变是Phe508(Delta F508)的缺失，这导致传统的高尔基体介导的胞吐和细胞表面表达的缺陷。我们报告说，Delta F508-CFTR表面的表达可以通过引导它到非传统的掌握依赖的分泌途径在体外和体内得到挽救。综合的分子和生理分析表明，与内质网应激相关的机制通过GRAP依赖的途径诱导ER核心糖基化野生型和Delta F508-CFTR的细胞表面转运。GRAP特定位点的磷酸化以及GRASH和CFTR之间基于PDZ的相互作用对于这种非常规的表面运输至关重要。值得注意的是，在Delta F508-CFTR小鼠中转基因表达GRAP可以恢复CFTR功能，并在没有明显毒性的情况下挽救小鼠的生存。这些发现为了解非常规蛋白质分泌是如何被激活的提供了洞察，并为囊性纤维化的治疗提供了一种潜在的治疗策略，可能还包括其他错误折叠的蛋白质引起的疾病。
The most prevalent disease-causing mutation of CFTR is the deletion of Phe508 (Delta F508), which leads to defects in conventional Golgi-mediated exocytosis and cell surface expression. We report that Delta F508-CFTR surface expression can be rescued in vitro and in vivo by directing it to an unconventional GRASP-dependent secretion pathway. An integrated molecular and physiological analysis indicates that mechanisms associated with ER stress induce cell surface trafficking of the ER core-glycosylated wild-type and Delta F508-CFTR via the GRASP-dependent pathway. Phosphorylation of a specific site of GRASP and the PDZ-based interaction between GRASP and CFTR are critical for this unconventional surface trafficking. Remarkably, transgenic expression of GRASP in Delta F508-CFTR mice restores CFTR function and rescues mouse survival without apparent toxicity. These findings provide insight into how unconventional protein secretion is activated, and offer a potential therapeutic strategy for the treatment of cystic fibrosis and perhaps diseases stemming from other misfolded proteins.