title: Calumenin contributes to ER-Ca2+homeostasis in bronchial epithelial cells expressing WT and F508del mutated CFTR and to F508del-CFTR retention.
abstract: Cystic Fibrosis (CF) is the most frequent fatal genetic disease in Caucasian populations. Mutations in the chloride channel CF Transmembrane Conductance Regulator (CFTR) gene are responsible for functional defects of the protein and multiple associated dysregulations. The most common mutation in patients with CF, F508del-CFTR, causes defective CFTR protein folding. Thus minimal levels of the receptor are expressed at the cell surface as the mutated CFTR is retained in the endoplasmic reticulum (ER) where it correlates with defective calcium (Ca2+) homeostasis. In this study, we discovered that the Ca2+binding protein Calumenin (CALU) is a key regulator in the maintenance of ER-Ca2+calcium homeostasis in both wild type and F508del-CFTR expressing cells. Calumenin modulates SERCA pump activity without drastically affecting ER-Ca2+concentration. In addition, reducing Calumenin expression in CF cells results in a partial restoration of CFTR activity, highlighting a potential function of Calumenin in CFTR maturation. These findings demonstrate a pivotal role for Calumenin in CF cells, providing insights into how modulation of Calumenin expression or activity may be used as a potential therapeutic tool to correct defects in F508del-CFTR.
authors.affiliation: INSERM U1078 « Génétique, Génomique fonctionnelle et biotechnologies », Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale, 29200 Brest, France.
authors.forename: Réginald
authors.initials: R
authors.lastname: Philippe
authors.affiliation: UMR_S 999, INSERM, Laboratoire d'Excellence (LabEx) en Recherche sur le Médicament et l'Innovation Thérapeutique (LERMIT), Centre Chirurgical Marie Lannelongue, Université Paris-Saclay, Le Plessis Robinson F-92350, France; Laboratoire Signalisation et Transport Ioniques Membranaires, Université Poitiers-CNRS, Pôle Biologie Santé, 1 rue George Bonnet, 86073 Poitiers Cedex, France; Department of Cell Physiology and Metabolism, Geneva Medical Center, 1, Rue Michel Servet, 1211 Geneva 4, Switzerland.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Antigny
authors.affiliation: INSERM U1078 « Génétique, Génomique fonctionnelle et biotechnologies », Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale, 29200 Brest, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Buscaglia
authors.affiliation: Laboratoire Signalisation et Transport Ioniques Membranaires, Université Poitiers-CNRS, Pôle Biologie Santé, 1 rue George Bonnet, 86073 Poitiers Cedex, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Norez
authors.affiliation: INSERM U1078 « Génétique, Génomique fonctionnelle et biotechnologies », Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale, 29200 Brest, France.
authors.forename: Florentin
authors.initials: F
authors.lastname: Huguet
authors.affiliation: Department of Cell Physiology and Metabolism, Geneva Medical Center, 1, Rue Michel Servet, 1211 Geneva 4, Switzerland.
authors.forename: Cyril
authors.initials: C
authors.lastname: Castelbou
authors.affiliation: INSERM U1078 « Génétique, Génomique fonctionnelle et biotechnologies », Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale, 29200 Brest, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Trouvé
authors.affiliation: Laboratoire Signalisation et Transport Ioniques Membranaires, Université Poitiers-CNRS, Pôle Biologie Santé, 1 rue George Bonnet, 86073 Poitiers Cedex, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Becq
authors.affiliation: Department of Cell Physiology and Metabolism, Geneva Medical Center, 1, Rue Michel Servet, 1211 Geneva 4, Switzerland.
authors.forename: Maud
authors.initials: M
authors.lastname: Frieden
authors.affiliation: INSERM U1078 « Génétique, Génomique fonctionnelle et biotechnologies », Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale, 29200 Brest, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Férec
authors.affiliation: INSERM U1078 « Génétique, Génomique fonctionnelle et biotechnologies », Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale, 29200 Brest, France. Electronic address: olivier.mignen@univ-brest.fr.
authors.forename: Olivier
authors.initials: O
authors.lastname: Mignen
mesh_terms: D001980:Bronchi / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans
chemical_list: C510527:CALU protein, human; D002135:Calcium-Binding Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D002118:Calcium
keywords: Calumenin; Cystic fibrosis; ER Ca(2+) homeostasis; F508del-CFTR; SERCA