Rescue of Δf508-CFTR trafficking via a GRASP-dependent unconventional secretion pathway

Heon Yung Gee, Shin Hye Noh, Bor Luen Tang, Kyung Hwan Kim, Min Goo Lee

Research output: Contribution to journalArticle

169 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)746-760
Number of pages15
JournalCell
Volume146
Issue number5
DOIs
Publication statusPublished - 2011 Sep 2

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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