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Cigarette Smoke Exposure Induces Retrograde Trafficking of CFTR to the Endoplasmic Reticulum

Lookup NU author(s): Abi Marklew, Waseema Patel, Dr Michael Gray

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

Chronic obstructive pulmonary disease (COPD), which is most commonly caused by cigarette smoke (CS) exposure, is the third leading cause of death worldwide. The cystic fibrosis transmembrane conductance regulator (CFTR) is an apical membrane anion channel that is widely expressed in epithelia throughout the body. In the airways, CFTR plays an important role in fluid homeostasis and helps flush mucus and inhaled pathogens/toxicants out of the lung. Inhibition of CFTR leads to mucus stasis and severe airway disease. CS exposure also inhibits CFTR, leading to the decreased anion secretion/hydration seen in COPD patients. However, the underlying mechanism is poorly understood. Here, we report that CS causes CFTR to be internalized in a clathrin/dynamin-dependent fashion. This internalization is followed by retrograde trafficking of CFTR to the endoplasmic reticulum. Although this internalization pathway has been described for bacterial toxins and cargo machinery, it has never been reported for mammalian ion channels. Furthermore, the rapid internalization of CFTR is dependent on CFTR dephosphorylation by calcineurin, a protein phosphatase that is upregulated by CS. These results provide new insights into the mechanism of CFTR internalization, and may help in the development of new therapies for CFTR correction and lung rehydration in patients with debilitating airway diseases such as COPD.

Publication metadata

Author(s): Marklew AJ, Patel W, Moore PJ, Tan CD, Smith AJ, Sassano MF, Gray MA, Tarran R

Publication type: Article

Publication status: Published

Journal: Scientific Reports

Year: 2019

Volume: 9

Issue: 1

Online publication date: 20/09/2019

Acceptance date: 12/08/2019

Date deposited: 01/10/2019

ISSN (electronic): 2045-2322

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/s41598-019-49544-9

DOI: 10.1038/s41598-019-49544-9

PubMed id: 31541117

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