title: Bafilomycin A1-sensitive pathway is required for the maturation of cystic fibrosis transmembrane conductance regulator.
abstract: Cystic fibrosis (CF) is the most common lethal genetic disease in Caucasians caused by the trafficking defects of CF transmembrane conductance regulator (CFTR), which is a cAMP-dependent Cl- channel at the plasma membrane. The trafficking pathway of CFTR is thought to be non-conventional because CFTR maturation is inhibited by the dysfunction of syntaxin 13, which is involved in protein recycling via endosomal pathway. In this study, to clarify whether the endosomal trafficking is required for CFTR maturation, we utilized a specific vacuolar H+-ATPase inhibitor, bafilomycin A1 (BafA1), which inhibits the protein trafficking from early endosome. Our data showed that low concentration of BafA1 (50 nM) decreased the expression of mature CFTR but induced the accumulation of immature CFTR in the juxta-nuclear region containing an early endosome marker. Pulse-chase analysis showed that BafA1 inhibited the maturation of CFTR, but it slightly stabilized immature CFTR. These results indicate that BafA1-sensitive pathway is required for CFTR maturation and emphasize that endosomal trafficking pathway might be involved in the maturation of CFTR.
authors.affiliation: Department of Molecular Medicine, Faculty of Medical and Pharmaceutical Sciences, 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: Yasuaki
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.forename: Tappei
authors.initials: T
authors.lastname: Takada
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shuto
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Suico
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kai
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D011992:Endosomes / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D015398:Signal Transduction; D014162:Transfection
chemical_list: D000935:Antifungal Agents; D018942:Macrolides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C040929:bafilomycin A1