Involvement of the Cdc42 pathway in CFTR post-translational turnover and in its plasma membrane stability in airway epithelial cells

PloS One
Romain Ferru-ClémentVincent Thoreau

Abstract

Cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel that is expressed on the apical plasma membrane (PM) of epithelial cells. The most common deleterious allele encodes a trafficking-defective mutant protein undergoing endoplasmic reticulum-associated degradation (ERAD) and presenting lower PM stability. In this study, we investigated the involvement of the Cdc42 pathway in CFTR turnover and trafficking in a human bronchiolar epithelial cell line (CFBE41o-) expressing wild-type CFTR. Cdc42 is a small GTPase of the Rho family that fulfils numerous cell functions, one of which is endocytosis and recycling process via actin cytoskeleton remodelling. When we treated cells with chemical inhibitors such as ML141 against Cdc42 and wiskostatin against the downstream effector N-WASP, we observed that CFTR channel activity was inhibited, in correlation with a decrease in CFTR amount at the cell surface and an increase in dynamin-dependent CFTR endocytosis. Anchoring of CFTR to the cortical cytoskeleton was then presumably impaired by actin disorganization. When we performed siRNA-mediated depletion of Cdc42, actin polymerization was not impacted, but we observed actin-independent consequences upon CFTR. Total...Continue Reading

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Citations

Dec 25, 2015·ELife·Ramanath Narayana HegdeAlberto Luini
Sep 19, 2017·Laboratory Investigation; a Journal of Technical Methods and Pathology·Zsolt FarkasKrisztina Takács-Vellai
Sep 10, 2020·Frontiers in Physiology·Richard BallwegTongli Zhang
Jan 7, 2021·Immunologic Research·Paria KashaniEyal Grunebaum

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Methods Mentioned

BETA
ubiquitination
transfection
immunoprecipitation
GTPases
pull-downs
GTPase
glycosylation
nucleotide exchange

Software Mentioned

GraphPad Prism
Scion Image

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