Rescue of ΔF508-CFTR Trafficking via a GRASP-Dependent Unconventional Secretion Pathway

The most prevalent disease-causing mutation of CFTR is the deletion of Phe508 (Delta F508), which leads to defects in conventional Golgi-mediated exocytosis and cell surface expression. We report that Delta F508-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 Delta F508-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 Delta F508-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.