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

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

ASJC Scopus subject areas

  • Cell Biology
  • Medicine(all)

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    Luciani, A., Villella, V. R., 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, 12(9), 863-875. https://doi.org/10.1038/ncb2090