title: Role of calnexin in the ER quality control and productive folding of CFTR; differential effect of calnexin knockout on wild-type and DeltaF508 CFTR.
abstract: 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, DeltaF508 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 DeltaF508 CFTR. Our data show that CNX knockout (KO) does not affect the biosynthetic processing, cellular localization or the Cl(-) channel function of DeltaF508 CFTR. Importantly, cAMP-induced Cl(-) current in colonic epithelium from CNX KO/DeltaF508 CFTR mice was comparable with that of DeltaF508 CFTR mice, indicating that CNX KO failed to rescue the ER retention of DeltaF508 CFTR in vivo. Moreover, we show that CNX assures the efficient expression of WT CFTR, but not DeltaF508 CFTR, by inhibiting the proteasomal degradation, indicating that CNX might stimulate the productive folding of WT CFTR, but not DeltaF508 CFTR, which has folding defects.
authors.affiliation: Department of Molecular Medicine, Graduate School of Medical and Pharmaceutical Sciences, Global COE "Cell Fate Regulation Research and Education Unit", Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Okiyoneda
authors.forename: Akiko
authors.initials: A
authors.lastname: Niibori
authors.forename: Kazutsune
authors.initials: K
authors.lastname: Harada
authors.forename: Taijun
authors.initials: T
authors.lastname: Kohno
authors.forename: Marek
authors.initials: M
authors.lastname: Michalak
authors.forename: Marek
authors.initials: M
authors.lastname: Duszyk
authors.forename: Ikuo
authors.initials: I
authors.lastname: Wada
authors.forename: Masahito
authors.initials: M
authors.lastname: Ikawa
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shuto
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Suico
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kai
mesh_terms: D000818:Animals; D037281:Calnexin / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004848:Epithelium / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D017510:Protein Folding; D017384:Sequence Deletion
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D037281:Calnexin