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

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229 Citations (Scopus)


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
Issue number5
Publication statusPublished - 2011 Sept 2

Bibliographical note

Funding Information:
We thank Shmuel Muallem, Hyun Woo Park, and Dong-Su Jang for helpful discussions and editorial assistance, and the Yonsei-Carl Zeiss Advanced Imaging Center, Yonsei Proteome Research Center, and the Mouse Division of Macrogen for technical assistance. This work was supported by grants 2011-0001178 and 2011-0016484 from the National Research Foundation of Korea funded by the Ministry of Education, Science, and Technology, Korea, and A030001 from the Korea Health 21 R&D Project, Ministry of Health and Welfare, Korea. B.L.T. is supported by an AcRF grant from the Ministry of Education of Singapore. H.Y.G. and S.H.N. performed the experiments, analyzed data, and wrote the paper. B.L.T. and K.H.K. assisted in performing experiments. M.G.L. designed and coordinated the study and wrote the paper.

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)


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