title: Phosphatidic acid metabolism regulates the intracellular trafficking and retrotranslocation of CFTR.
abstract: The cystic fibrosis transmembrane conductance regulator (CFTR) is transported to the plasma membrane from endoplasmic reticulum (ER) through the Golgi. Crucial to these trafficking events is the role of not only the proteinous factors but also the membrane lipids. However, the involvement of lipids, such as phospholipids, on the regulation of CFTR trafficking has been largely unexplored. Here, we show that the inhibition of phospholipase D (PLD)-mediated phosphatidic acid (PA) formation by 1-butanol inhibited the maturation and export of CFTR from the ER. Exogenously added PA reversed these effects. Moreover, knock down of PLD1 by small interfering RNA decreased the expression of mature CFTR. Interestingly, sustaining the level of PA, by the addition of excess PA in the presence of PA phosphatase inhibitor, attenuated the transport of CFTR from the Golgi to plasma membrane and the retrograde transport of DeltaF508 CFTR to the cytoplasm, a necessary step for the ER-associated degradation of DeltaF508 CFTR. These results indicated that the metabolism of PA modulated the intracellular dynamics and trafficking of CFTR.
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Global COE Cell Fate Regulation Research and Education Unit, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Okiyoneda
authors.forename: Kazutsune
authors.initials: K
authors.lastname: Harada
authors.forename: Keiko
authors.initials: K
authors.lastname: Ueno
authors.forename: Takuya
authors.initials: T
authors.lastname: Sugahara
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yamashita
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; D002460:Cell Line; D006224:Cricetinae; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D017353:Gene Deletion; D006056:Golgi Apparatus / Q000378:metabolism; D010711:Phosphatidate Phosphatase / Q000378:metabolism; D010712:Phosphatidic Acids / Q000378:metabolism*; D010739:Phospholipase D / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D021381:Protein Transport
chemical_list: D010712:Phosphatidic Acids; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D010711:Phosphatidate Phosphatase; D010739:Phospholipase D