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Cell. 2011 Sep 2;146(5):746-60. doi: 10.1016/j.cell.2011.07.021.

Rescue of ΔF508-CFTR trafficking via a GRASP-dependent unconventional secretion pathway.

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1
Department of Pharmacology, Brain Korea 21 Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 120-752, Korea.

Abstract

The most prevalent disease-causing mutation of CFTR is the deletion of Phe508 (ΔF508), which leads to defects in conventional Golgi-mediated exocytosis and cell surface expression. We report that ΔF508-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 ΔF508-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 ΔF508-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.

PMID:
21884936
DOI:
10.1016/j.cell.2011.07.021
[Indexed for MEDLINE]
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