Journal article
Cigarette smoking is a secondary cause of folliculin loss
Thorax, Vol.78(4), pp.402-408
04/01/2023
DOI: 10.1136/thoraxjnl-2021-217197
PMID: 35301243
Abstract
BackgroundBirt-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.ObjectiveGiven that COPD often shares structural features with BHD, we investigated the link between COPD, cigarette smoke (CS) exposure and FLCN expression.MethodsWe 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.ResultsWe 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.ConclusionsOur study demonstrates that CS exposure is a secondary cause of FLCN deficiency due to the enhanced proteolysis, which promoted airway epithelial cell death.
Details
- Title: Subtitle
- Cigarette smoking is a secondary cause of folliculin loss
- Creators
- Xiuying Li - University of PittsburghYandong Lai - University of PittsburghZachary Lane - University of PittsburghHilary Strollo - University of PittsburghKazuya Tanimura - University of PittsburghJohn C Sembrat - University of PittsburghChunbin Zou - University of PittsburghMichael M Myerburg - University of PittsburghMauricio Rojas - The Ohio State UniversitySteven Shapiro - University of PittsburghYu Jiang - University of PittsburghToru Nyunoya - University of Pittsburgh
- Resource Type
- Journal article
- Publication Details
- Thorax, Vol.78(4), pp.402-408
- DOI
- 10.1136/thoraxjnl-2021-217197
- PMID
- 35301243
- NLM abbreviation
- Thorax
- ISSN
- 0040-6376
- eISSN
- 1468-3296
- Publisher
- BMJ Publishing Group Ltd and British Thoracic Society
- Number of pages
- 7
- Grant note
- CX000105; CX001048 / U.S. Department of Veterans Affairs (http://dx.doi.org/10.13039/100000738) 19TPA34830061 / American Heart Association (http://dx.doi.org/10.13039/100000968) R01 HL149719 / National Heart, Lung, and Blood Institute (http://dx.doi.org/10.13039/100000050) GM132127 / National Institute of General Medical Sciences (http://dx.doi.org/10.13039/100000057)
- Language
- English
- Date published
- 04/01/2023
- Academic Unit
- Internal Medicine
- Record Identifier
- 9985214107402771
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