RT Journal Article
SR Electronic
T1 Cigarette smoking is a secondary cause of folliculin loss
JF Thorax
JO Thorax
FD BMJ Publishing Group Ltd and British Thoracic Society
SP thoraxjnl-2021-217197
DO 10.1136/thoraxjnl-2021-217197
A1 Li, Xiuying
A1 Lai, Yandong
A1 Lane, Zachary
A1 Strollo, Hilary
A1 Tanimura, Kazuya
A1 Sembrat, John C
A1 Zou, Chunbin
A1 Myerburg, Michael M
A1 Rojas, Mauricio
A1 Shapiro, Steven
A1 Jiang, Yu
A1 Nyunoya, Toru
YR 2022
UL http://thorax.bmj.com/content/early/2022/03/29/thoraxjnl-2021-217197.abstract
AB Background Birt-Hogg-Dubé syndrome (BHD) is a clinical syndrome manifesting with cystic lung disease and pneumothorax. Features of BHD result from the loss-of-function mutations of the folliculin (FLCN) gene. Chronic obstructive pulmonary disease (COPD), characterised by an irreversible airflow limitation, is primarily caused by cigarette smoking.Objective Given that COPD often shares structural features with BHD, we investigated the link between COPD, cigarette smoke (CS) exposure and FLCN expression.Methods We measured the expression of FLCN in human COPD lungs and CS-exposed mouse lungs, as well as in CS extract (CSE)-exposed immortalised human airway epithelial cells by immunoblotting.Results We found that the lung FLCN protein levels in smokers with COPD and CS exposure mice exhibit a marked decrease compared with smokers without COPD and room air exposure mice, respectively. We confirmed CS induced degradation of FLCN in immortalised human bronchial epithelial Beas-2B cells via ubiquitin proteasome system. Further, siRNA targeting FLCN enhanced CSE-induced cytotoxicity. By contrast, FLCN overexpression protected cells from CSE-induced cytotoxicity. We found that FBXO23, the ubiquitin E3 ligase subunit, specifically binds to and targets FLCN for degradation. Inhibition of ATM (ataxia‐telangiectasia mutated) attenuated CSE induced FLCN degradation, suggesting a role of ATM in FLCN proteolysis. We further confirmed that the mutant of major FLCN phosphorylation site serine 62A is resistant to CSE-induced degradation and cytotoxicity.Conclusions Our study demonstrates that CS exposure is a secondary cause of FLCN deficiency due to the enhanced proteolysis, which promoted airway epithelial cell death.All data relevant to the study are included in the article or uploaded as supplementary information.