In vivo model for modulators of CFTR^ΔF508 misfolding

Cystic fibrosis (CF) is most commonly caused by deletion of a single amino acid (ΔF508) in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. This mutation causes protein misfolding and disrupts many cellular functions. Many models of CFTR^ΔF508 misfolding exist, but none are amenable to rapid genetic dissection of the pathways that are disrupted by the mutation. He et al. now report a fluorescence-based C. elegans model that will enable such studies. They show that expressing the ΔF508 mutation in P-glycoprotein-3 (PGP-3), which is similar to mammalian CFTR, disrupts protein folding and prevents CFTR trafficking to the apical membrane of epithelial cells; this resembles the effects of the CFTR^ΔF508 mutation, and is rescued by the same treatments as in mammalian cells. This model will enable unbiased genetic screens for modulators of CFTR misfolding and hopefully uncover new therapeutic targets. Page 930