Disease-relevant proteostasis regulation of cystic fibrosis transmembrane conductance regulator

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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.

Autore Pugliese

Tutti gli autori

  • Villella VR , Esposito S , Bruscia EM , Vicinanza M , Cenci S , Guido S , Pettoello-Mantovani M , Carnuccio R , De Matteis MA , Luini A , Maiuri MC , Raia V , Kroemer G , Maiuri L.

Titolo volume/Rivista

CELL DEATH AND DIFFERENTIATION

Anno di pubblicazione

2013

ISSN

1350-9047

ISBN

Non Disponibile

Numero di citazioni Wos

12

Ultimo Aggiornamento Citazioni

Non Disponibile

Numero di citazioni Scopus

11

Ultimo Aggiornamento Citazioni

Non Disponibile

Settori ERC

Non Disponibile

Codici ASJC

Non Disponibile