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

      1 , , , ,
      Cell
      Elsevier BV

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          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.

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          Author and article information

          Journal
          Cell
          Cell
          Elsevier BV
          1097-4172
          0092-8674
          Sep 02 2011
          : 146
          : 5
          Affiliations
          [1 ] Department of Pharmacology, Brain Korea 21 Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 120-752, Korea.
          Article
          S0092-8674(11)00819-1
          10.1016/j.cell.2011.07.021
          21884936
          30f86c86-91e6-4e53-aade-2e8ddd1ec459
          Copyright © 2011 Elsevier Inc. All rights reserved.
          History

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