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

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

Research output: Contribution to journalArticle

285 Citations (Scopus)

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-CFTR F508del 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 Cftr F508del homozygous mice, and in human CF nasal biopsies. Restoring beclin 1 or knocking down p62 rescued the trafficking of CFTR F508del to the cell surface. These data link the CFTR defect to autophagy deficiency, leading to the accumulation of protein aggregates and to lung inflammation.

Original languageEnglish
Pages (from-to)863-875
Number of pages13
JournalNature Cell Biology
Volume12
Issue number9
DOIs
Publication statusPublished - Sep 2010

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Cystic Fibrosis Transmembrane Conductance Regulator
Autophagy
Cystic Fibrosis
Reactive Oxygen Species
Pneumonia
Cystamine
Phosphatidylinositol 3-Kinase
Inborn Genetic Diseases
Electron Transport Complex III
Green Fluorescent Proteins
Nose
Endoplasmic Reticulum
Beclin-1
Fibrosis
Up-Regulation
Down-Regulation
Epithelium
Antioxidants
Phenotype
Biopsy

ASJC Scopus subject areas

  • Cell Biology
  • Medicine(all)

Cite this

Luciani, A., Villella, V. R., Esposito, S., Brunetti-Pierri, N., Medina, D., Settembre, C., ... Maiuri, L. (2010). Defective CFTR induces aggresome formation and lung inflammation in cystic fibrosis through ROS-mediated autophagy inhibition. Nature Cell Biology, 12(9), 863-875. https://doi.org/10.1038/ncb2090

Defective CFTR induces aggresome formation and lung inflammation in cystic fibrosis through ROS-mediated autophagy inhibition. / 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; Raia, Valeria; Ballabio, Andrea; Maiuri, Luigi.

In: Nature Cell Biology, Vol. 12, No. 9, 09.2010, p. 863-875.

Research output: Contribution to journalArticle

Luciani, A, Villella, VR, Esposito, S, Brunetti-Pierri, N, Medina, D, Settembre, C, Gavina, M, Pulze, L, Giardino, I, Pettoello-Mantovani, M, D'Apolito, M, Guido, S, Masliah, E, Spencer, B, Quaratino, S, Raia, V, Ballabio, A & Maiuri, L 2010, 'Defective CFTR induces aggresome formation and lung inflammation in cystic fibrosis through ROS-mediated autophagy inhibition', Nature Cell Biology, vol. 12, no. 9, pp. 863-875. https://doi.org/10.1038/ncb2090
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 ; Raia, Valeria ; Ballabio, Andrea ; Maiuri, Luigi. / Defective CFTR induces aggresome formation and lung inflammation in cystic fibrosis through ROS-mediated autophagy inhibition. In: Nature Cell Biology. 2010 ; Vol. 12, No. 9. pp. 863-875.
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