SiRNA calnexin promotes endogenous F508del-CFTR trafficking

Tezacaftor/Ivacaftor in Subjects with Cystic Fibrosis and F508del/F508del-CFTR or F508del/G551D-CFTR.

RATIONALE Tezacaftor (formerly VX-661) is an investigational small molecule that improves processing and trafficking of the cystic fibrosis transmembrane conductance regulator (CFTR) in vitro, and improves CFTR function alone and in combination with ivacaftor. OBJECTIVES To evaluate the safety and efficacy of tezacaftor monotherapy and of tezacaftor/ivacaftor combination therapy in subjects w...

Most F508del-CFTR is targeted to degradation at an early folding checkpoint and independently of calnexin.

Biosynthesis and folding of multidomain transmembrane proteins is a complex process. Structural fidelity is monitored by endoplasmic reticulum (ER) quality control involving the molecular chaperone calnexin. Retained misfolded proteins undergo ER-associated degradation (ERAD) through the ubiquitin-proteasome pathway. Our data show that the major degradation pathway of the cystic fibrosis transm...

Induction of HSP70 promotes DF508 CFTR trafficking

Choo-Kang, Lee R., and Pamela L. Zeitlin. Induction of HSP70 promotes DF508 CFTR trafficking. Am J Physiol Lung Cell Mol Physiol 281: L58–L68, 2001.— The DF508 cystic fibrosis transmembrane conductance regulator (CFTR) is a temperature-sensitive trafficking mutant that is detected as an immature 160-kDa form (band B) in gel electrophoresis. The goal of this study was to test the hypothesis that...

Correction of F508del-CFTR trafficking by the sponge alkaloid latonduine is modulated by interaction with PARP.

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause CF. The most common mutation, F508 deletion, causes CFTR misfolding and endoplasmic reticulum retention, preventing it from trafficking to the cell surface. One approach to CF treatment is to identify compounds that correct the trafficking defect. We screened a marine extract collection and, after extract, de...

Structural analogue of sildenafil identified as a novel corrector of the F508del-CFTR trafficking defect