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Cigarette smoking is a secondary cause of folliculin loss
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 lim...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9612398/ https://www.ncbi.nlm.nih.gov/pubmed/35301243 http://dx.doi.org/10.1136/thoraxjnl-2021-217197 |
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author | Li, Xiuying Lai, Yandong Lane, Zachary Strollo, Hilary Tanimura, Kazuya Sembrat, John C Zou, Chunbin Myerburg, Michael M Rojas, Mauricio Shapiro, Steven Jiang, Yu Nyunoya, Toru |
author_facet | Li, Xiuying Lai, Yandong Lane, Zachary Strollo, Hilary Tanimura, Kazuya Sembrat, John C Zou, Chunbin Myerburg, Michael M Rojas, Mauricio Shapiro, Steven Jiang, Yu Nyunoya, Toru |
author_sort | Li, Xiuying |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9612398 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-96123982023-04-12 Cigarette smoking is a secondary cause of folliculin loss Li, Xiuying Lai, Yandong Lane, Zachary Strollo, Hilary Tanimura, Kazuya Sembrat, John C Zou, Chunbin Myerburg, Michael M Rojas, Mauricio Shapiro, Steven Jiang, Yu Nyunoya, Toru Thorax Smoking 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. BMJ Publishing Group 2023-04 2022-03-17 /pmc/articles/PMC9612398/ /pubmed/35301243 http://dx.doi.org/10.1136/thoraxjnl-2021-217197 Text en © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) . |
spellingShingle | Smoking Li, Xiuying Lai, Yandong Lane, Zachary Strollo, Hilary Tanimura, Kazuya Sembrat, John C Zou, Chunbin Myerburg, Michael M Rojas, Mauricio Shapiro, Steven Jiang, Yu Nyunoya, Toru Cigarette smoking is a secondary cause of folliculin loss |
title | Cigarette smoking is a secondary cause of folliculin loss |
title_full | Cigarette smoking is a secondary cause of folliculin loss |
title_fullStr | Cigarette smoking is a secondary cause of folliculin loss |
title_full_unstemmed | Cigarette smoking is a secondary cause of folliculin loss |
title_short | Cigarette smoking is a secondary cause of folliculin loss |
title_sort | cigarette smoking is a secondary cause of folliculin loss |
topic | Smoking |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9612398/ https://www.ncbi.nlm.nih.gov/pubmed/35301243 http://dx.doi.org/10.1136/thoraxjnl-2021-217197 |
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