Role of calnexin in the ER quality control and productive folding of CFTR; differential effect of calnexin knockout on wild-type and ΔF508 CFTR

Cystic fibrosis (CF) is caused by the mutation in CF transmembrane conductance regulator (CFTR), a cAMP-dependent Cl− channel at the plasma membrane of epithelium. The most common mutant, ΔF508 CFTR, has competent Cl− channel function, but fails to express at the plasma membrane since it is retained in the endoplasmic reticulum (ER) by the ER quality control system. Here, we show that calnexin (CNX) is not necessary for the ER retention of ΔF508 CFTR. Our data show that CNX knockout (KO) does not affect the biosynthetic processing, cellular localization or the Cl− channel function of ΔF508 CFTR. Importantly, cAMP-induced Cl− current in colonic epithelium from CNX KO/ΔF508 CFTR mice was comparable with that of ΔF508 CFTR mice, indicating that CNX KO failed to rescue the ER retention of ΔF508 CFTR in vivo. Moreover, we show that CNX assures the efficient expression of WT CFTR, but not ΔF508 CFTR, by inhibiting the proteasomal degradation, indicating that CNX might stimulate the productive folding of WT CFTR, but not ΔF508 CFTR, which has folding defects.