title: Genetic Inhibition Of The Ubiquitin Ligase Rnf5 Attenuates Phenotypes Associated To F508del Cystic Fibrosis Mutation.
abstract: Cystic fibrosis (CF) is caused by mutations in the CFTR chloride channel. Deletion of phenylalanine 508 (F508del), the most frequent CF mutation, impairs CFTR trafficking and gating. F508del-CFTR mistrafficking may be corrected by acting directly on mutant CFTR itself or by modulating expression/activity of CFTR-interacting proteins, that may thus represent potential drug targets. To evaluate possible candidates for F508del-CFTR rescue, we screened a siRNA library targeting known CFTR interactors. Our analysis identified RNF5 as a protein whose inhibition promoted significant F508del-CFTR rescue and displayed an additive effect with the investigational drug VX-809. Significantly, RNF5 loss in F508del-CFTR transgenic animals ameliorated intestinal malabsorption and concomitantly led to an increase in CFTR activity in intestinal epithelial cells. In addition, we found that RNF5 is differentially expressed in human bronchial epithelia from CF vs. control patients. Our results identify RNF5 as a target for therapeutic modalities to antagonize mutant CFTR proteins.
authors.affiliation: Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Tomati
authors.affiliation: Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Elvira
authors.initials: E
authors.lastname: Sondo
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia, Genova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Armirotti
authors.affiliation: Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Caci
authors.affiliation: Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Pesce
authors.affiliation: Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Marini
authors.affiliation: Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Ambra
authors.initials: A
authors.lastname: Gianotti
authors.affiliation: The Burnham Institute for Medical Research, La Jolla, California, USA.
authors.forename: Young Ju
authors.initials: YJ
authors.lastname: Jeon
authors.affiliation: IRCCS AOU San Martino-IST, Genova, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Cilli
authors.affiliation: Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Pistorio
authors.affiliation: 1] IRCCS AOU San Martino-IST, Genova, Italy [2] Anatomic Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics, University of Genova, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Mastracci
authors.affiliation: 1] Istituto Giannina Gaslini, Genova, Italy [2] DINOGMI Department, University of Genova, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Ravazzolo
authors.affiliation: Cell Biology Department, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Bob
authors.initials: B
authors.lastname: Scholte
authors.affiliation: The Burnham Institute for Medical Research, La Jolla, California, USA.
authors.forename: Ze'ev
authors.initials: Z
authors.lastname: Ronai
authors.affiliation: Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Luis J V
authors.initials: LJ
authors.lastname: Galietta
authors.affiliation: Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Pedemonte
mesh_terms: D000483:Alleles; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D003550:Cystic Fibrosis / Q000235:genetics* / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004386:Duodenum / Q000378:metabolism; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D056726:Genetic Association Studies; D005838:Genotype; D006031:Glycosylation; D006801:Humans; D018345:Mice, Knockout; D010641:Phenotype; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D017384:Sequence Deletion; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C111501:RNF5 protein, human; D044767:Ubiquitin-Protein Ligases