The University of Southampton
University of Southampton Institutional Repository

Defective CFTR induces aggresome formation and lung inflammation in cystic fibrosis through ROS-mediated autophagy inhibition

Defective CFTR induces aggresome formation and lung inflammation in cystic fibrosis through ROS-mediated autophagy inhibition
Defective CFTR induces aggresome formation and lung inflammation in cystic fibrosis through ROS-mediated autophagy inhibition
Accumulation of unwanted/misfolded proteins in aggregates has been observed in airways of patients with cystic fibrosis (CF), a life-threatening genetic disorder caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). Here we show how the defective CFTR results in defective autophagy and decreases the clearance of aggresomes. Defective CFTR-induced upregulation of reactive oxygen species (ROS) and tissue transglutaminase (TG2) drive the crosslinking of beclin 1, leading to sequestration of phosphatidylinositol-3-kinase (PI(3)K) complex III and accumulation of p62, which regulates aggresome formation. Both CFTR knockdown and the overexpression of green fluorescent protein (GFP)-tagged-CFTRF508del induce beclin 1 downregulation and defective autophagy in non-CF airway epithelia through the ROS–TG2 pathway. Restoration of beclin 1 and autophagy by either beclin 1 overexpression, cystamine or antioxidants rescues the localization of the beclin 1 interactome to the endoplasmic reticulum and reverts the CF airway phenotype in vitro, in vivo in Scnn1b-transgenic and CftrF508del homozygous mice, and in human CF nasal biopsies. Restoring beclin 1 or knocking down p62 rescued the trafficking of CFTRF508del to the cell surface. These data link the CFTR defect to autophagy deficiency, leading to the accumulation of protein aggregates and to lung inflammation.

1465-7392
863-875
Luciani, Alessandro
3b273f51-9164-415b-9aec-fa8fd5976734
Villella, Valeria Rachela
b6ce5642-7496-445c-8de4-4fd9097ddc3c
Esposito, Speranza
b0911d45-c46f-4f2d-8e10-f043145b5b20
Brunetti-Pierri, Nicola
9d72f71c-cb39-4026-bb9d-0c3d85703ab4
Medina, Diego
d9dda6a7-3f31-44b7-bdfb-3c7c0bbd23a8
Settembre, Carmine
c32e1129-c0c4-4c9e-915c-c233805fdad3
Gavina, Manuela
61b145ab-dd7d-4d1e-9234-51921acf03cb
Pulze, Laura
28c84962-fa0f-4994-a345-4e37a848a439
Giardino, Ida
268bec37-e352-476b-987b-5237e836e7c2
Pettoello-Mantovani, Massimo
80024b87-7896-4138-8372-3756a3923871
D'Apolito, Maria
62cfe765-b929-4ab9-bed2-d1a2d7691073
Guido, Stefano
d2b588e6-1c0c-44ac-93af-352f0a06898f
Masliah, Eliezer
1274303d-f706-49aa-a2dc-2ce734855221
Spencer, Brian
e525f34b-e1fa-4a65-92d3-2f4bfb7453f6
Quaratino, Sonia
a17d78fe-6c03-4775-83e3-53f9d511ae70
Raisa, Valeria
e0f67e12-7fce-47f3-90e7-0817d926221f
Ballabio, Andrea
1cf435be-4dba-4d0f-a67b-6cbb8469f7fb
Maiuri, Luigi
999bc98b-70b2-4b19-ad2e-788f7f531f61
Luciani, Alessandro
3b273f51-9164-415b-9aec-fa8fd5976734
Villella, Valeria Rachela
b6ce5642-7496-445c-8de4-4fd9097ddc3c
Esposito, Speranza
b0911d45-c46f-4f2d-8e10-f043145b5b20
Brunetti-Pierri, Nicola
9d72f71c-cb39-4026-bb9d-0c3d85703ab4
Medina, Diego
d9dda6a7-3f31-44b7-bdfb-3c7c0bbd23a8
Settembre, Carmine
c32e1129-c0c4-4c9e-915c-c233805fdad3
Gavina, Manuela
61b145ab-dd7d-4d1e-9234-51921acf03cb
Pulze, Laura
28c84962-fa0f-4994-a345-4e37a848a439
Giardino, Ida
268bec37-e352-476b-987b-5237e836e7c2
Pettoello-Mantovani, Massimo
80024b87-7896-4138-8372-3756a3923871
D'Apolito, Maria
62cfe765-b929-4ab9-bed2-d1a2d7691073
Guido, Stefano
d2b588e6-1c0c-44ac-93af-352f0a06898f
Masliah, Eliezer
1274303d-f706-49aa-a2dc-2ce734855221
Spencer, Brian
e525f34b-e1fa-4a65-92d3-2f4bfb7453f6
Quaratino, Sonia
a17d78fe-6c03-4775-83e3-53f9d511ae70
Raisa, Valeria
e0f67e12-7fce-47f3-90e7-0817d926221f
Ballabio, Andrea
1cf435be-4dba-4d0f-a67b-6cbb8469f7fb
Maiuri, Luigi
999bc98b-70b2-4b19-ad2e-788f7f531f61

Luciani, Alessandro, Villella, Valeria Rachela, Esposito, Speranza, Brunetti-Pierri, Nicola, Medina, Diego, Settembre, Carmine, Gavina, Manuela, Pulze, Laura, Giardino, Ida, Pettoello-Mantovani, Massimo, D'Apolito, Maria, Guido, Stefano, Masliah, Eliezer, Spencer, Brian, Quaratino, Sonia, Raisa, Valeria, Ballabio, Andrea and Maiuri, Luigi (2010) Defective CFTR induces aggresome formation and lung inflammation in cystic fibrosis through ROS-mediated autophagy inhibition. Nature Cell Biology, 12 (9), 863-875. (doi:10.1038/ncb2090). (PMID:20711182)

Record type: Article

Abstract

Accumulation of unwanted/misfolded proteins in aggregates has been observed in airways of patients with cystic fibrosis (CF), a life-threatening genetic disorder caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). Here we show how the defective CFTR results in defective autophagy and decreases the clearance of aggresomes. Defective CFTR-induced upregulation of reactive oxygen species (ROS) and tissue transglutaminase (TG2) drive the crosslinking of beclin 1, leading to sequestration of phosphatidylinositol-3-kinase (PI(3)K) complex III and accumulation of p62, which regulates aggresome formation. Both CFTR knockdown and the overexpression of green fluorescent protein (GFP)-tagged-CFTRF508del induce beclin 1 downregulation and defective autophagy in non-CF airway epithelia through the ROS–TG2 pathway. Restoration of beclin 1 and autophagy by either beclin 1 overexpression, cystamine or antioxidants rescues the localization of the beclin 1 interactome to the endoplasmic reticulum and reverts the CF airway phenotype in vitro, in vivo in Scnn1b-transgenic and CftrF508del homozygous mice, and in human CF nasal biopsies. Restoring beclin 1 or knocking down p62 rescued the trafficking of CFTRF508del to the cell surface. These data link the CFTR defect to autophagy deficiency, leading to the accumulation of protein aggregates and to lung inflammation.

This record has no associated files available for download.

More information

Published date: 15 August 2010

Identifiers

Local EPrints ID: 181385
URI: http://eprints.soton.ac.uk/id/eprint/181385
ISSN: 1465-7392
PURE UUID: 96f0f7f4-c0d4-4d41-ba7a-0a8cf17cda64

Catalogue record

Date deposited: 18 Apr 2011 12:56
Last modified: 14 Mar 2024 02:55

Export record

Altmetrics

Contributors

Author: Alessandro Luciani
Author: Valeria Rachela Villella
Author: Speranza Esposito
Author: Nicola Brunetti-Pierri
Author: Diego Medina
Author: Carmine Settembre
Author: Manuela Gavina
Author: Laura Pulze
Author: Ida Giardino
Author: Massimo Pettoello-Mantovani
Author: Maria D'Apolito
Author: Stefano Guido
Author: Eliezer Masliah
Author: Brian Spencer
Author: Sonia Quaratino
Author: Valeria Raisa
Author: Andrea Ballabio
Author: Luigi Maiuri

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×