Rescue of ΔF508-CFTR trafficking via a GRASP-dependent unconventional secretion pathway
- PMID: 21884936
- DOI: 10.1016/j.cell.2011.07.021
Rescue of ΔF508-CFTR trafficking via a GRASP-dependent unconventional secretion pathway
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.
Copyright © 2011 Elsevier Inc. All rights reserved.
Similar articles
-
Monomerization and ER Relocalization of GRASP Is a Requisite for Unconventional Secretion of CFTR.Traffic. 2016 Jul;17(7):733-53. doi: 10.1111/tra.12403. Epub 2016 May 18. Traffic. 2016. PMID: 27062250
-
Sec16A is critical for both conventional and unconventional secretion of CFTR.Sci Rep. 2017 Jan 9;7:39887. doi: 10.1038/srep39887. Sci Rep. 2017. PMID: 28067262 Free PMC article.
-
Base treatment corrects defects due to misfolding of mutant cystic fibrosis transmembrane conductance regulator.Gastroenterology. 2005 Dec;129(6):1979-90. doi: 10.1053/j.gastro.2005.08.049. Gastroenterology. 2005. PMID: 16344066
-
Unconventional Protein Secretion in Animal Cells.Methods Mol Biol. 2016;1459:31-46. doi: 10.1007/978-1-4939-3804-9_2. Methods Mol Biol. 2016. PMID: 27665549 Review.
-
Unconventional secretion: a stress on GRASP.Curr Opin Cell Biol. 2011 Aug;23(4):498-504. doi: 10.1016/j.ceb.2011.04.005. Epub 2011 May 14. Curr Opin Cell Biol. 2011. PMID: 21571519 Review.
Cited by
-
Role of canonical and noncanonical autophagy pathways in shaping the life journey of B cells.Front Immunol. 2024 Jul 30;15:1426204. doi: 10.3389/fimmu.2024.1426204. eCollection 2024. Front Immunol. 2024. PMID: 39139569 Free PMC article. Review.
-
Conventional and Unconventional Protein Secretion in Yeast and Animal Cells.Methods Mol Biol. 2024;2841:1-17. doi: 10.1007/978-1-0716-4059-3_1. Methods Mol Biol. 2024. PMID: 39115761 Review.
-
Golgi defect as a major contributor to lysosomal dysfunction.Front Cell Dev Biol. 2024 Apr 24;12:1386149. doi: 10.3389/fcell.2024.1386149. eCollection 2024. Front Cell Dev Biol. 2024. PMID: 38721528 Free PMC article. Review.
-
COPII cage assembly factor Sec13 integrates information flow regulating endomembrane function in response to human variation.Sci Rep. 2024 May 3;14(1):10160. doi: 10.1038/s41598-024-60687-2. Sci Rep. 2024. PMID: 38698045 Free PMC article.
-
Chloride/Multiple Anion Exchanger SLC26A Family: Systemic Roles of SLC26A4 in Various Organs.Int J Mol Sci. 2024 Apr 10;25(8):4190. doi: 10.3390/ijms25084190. Int J Mol Sci. 2024. PMID: 38673775 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases