title: Disease-relevant proteostasis regulation of cystic fibrosis transmembrane conductance regulator.
abstract: Mismanaged protein trafficking by the proteostasis network contributes to several conformational diseases, including cystic fibrosis, the most frequent lethal inherited disease in Caucasians. Proteostasis regulators, as cystamine, enable the beneficial action of cystic fibrosis transmembrane conductance regulator (CFTR) potentiators in ΔF508-CFTR airways beyond drug washout. Here we tested the hypothesis that functional CFTR protein can sustain its own plasma membrane (PM) stability. Depletion or inhibition of wild-type CFTR present in bronchial epithelial cells reduced the availability of the small GTPase Rab5 by causing Rab5 sequestration within the detergent-insoluble protein fraction together with its accumulation in aggresomes. CFTR depletion decreased the recruitment of the Rab5 effector early endosome antigen 1 to endosomes, thus reducing the local generation of phosphatidylinositol-3-phosphate. This diverts recycling of surface proteins, including transferrin receptor and CFTR itself. Inhibiting CFTR function also resulted in its ubiquitination and interaction with SQSTM1/p62 at the PM, favoring its disposal. Addition of cystamine prevented the recycling defect of CFTR by enhancing BECN1 expression and reducing SQSTM1 accumulation. Our results unravel an unexpected link between CFTR protein and function, the latter regulating the levels of CFTR surface expression in a positive feed-forward loop, and highlight CFTR as a pivot of proteostasis in bronchial epithelial cells.
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, European Institute for Research in Cystic Fibrosis, Milan 20132, Italy.
authors.forename: V R
authors.initials: VR
authors.lastname: Villella
authors.forename: S
authors.initials: S
authors.lastname: Esposito
authors.forename: E M
authors.initials: EM
authors.lastname: Bruscia
authors.forename: M
authors.initials: M
authors.lastname: Vicinanza
authors.forename: S
authors.initials: S
authors.lastname: Cenci
authors.forename: S
authors.initials: S
authors.lastname: Guido
authors.forename: M
authors.initials: M
authors.lastname: Pettoello-Mantovani
authors.forename: R
authors.initials: R
authors.lastname: Carnuccio
authors.forename: M A
authors.initials: MA
authors.lastname: De Matteis
authors.forename: A
authors.initials: A
authors.lastname: Luini
authors.forename: M C
authors.initials: MC
authors.lastname: Maiuri
authors.forename: V
authors.initials: V
authors.lastname: Raia
authors.forename: G
authors.initials: G
authors.lastname: Kroemer
authors.forename: L
authors.initials: L
authors.lastname: Maiuri
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D000071186:Beclin-1; D001980:Bronchi / Q000473:pathology / Q000503:physiopathology*; D002460:Cell Line; D002462:Cell Membrane / Q000502:physiology*; D003550:Cystic Fibrosis / Q000503:physiopathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000502:physiology*; D004847:Epithelial Cells / Q000473:pathology / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology; D009154:Mutation / Q000235:genetics; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology; D057165:Proteostasis Deficiencies / Q000503:physiopathology*; D011990:Receptors, Transferrin / Q000502:physiology; D000071456:Sequestosome-1 Protein; D020696:rab5 GTP-Binding Proteins / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D011990:Receptors, Transferrin; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D010744:Phosphoric Monoester Hydrolases; C061816:phosphatidylinositol-3-phosphatase; D020696:rab5 GTP-Binding Proteins