Cigarette smoking is a secondary cause of folliculin loss.
Cigarette smoking is a secondary cause of folliculin loss.
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birt - hogg - dub<s:1>综合征（BHD）是一种以肺囊性疾病和气胸为表现的临床综合征。BHD的特征源于卵泡蛋白（FLCN）基因的功能缺失突变。慢性阻塞性肺疾病（COPD）主要由吸烟引起，其特征是不可逆的气流限制。鉴于COPD通常与BHD具有相同的结构特征，我们研究了COPD、香烟烟雾（CS）暴露和FLCN表达之间的联系。我们通过免疫印迹法测量了FLCN在人类COPD肺和CS暴露的小鼠肺中的表达，以及在CS提取物（CSE）暴露的永生化人气道上皮细胞中的表达。我们发现，与非COPD吸烟者和室内空气暴露小鼠相比，COPD吸烟者和CS暴露小鼠的肺FLCN蛋白水平分别显著降低。我们通过泛素蛋白酶体系统证实了CS诱导永生化人支气管上皮细胞Beas-2B中FLCN的降解。此外，靶向FLCN的siRNA增强了cse诱导的细胞毒性。相比之下，FLCN过表达保护细胞免受cse诱导的细胞毒性。我们发现FBXO23，泛素E3连接酶亚基，特异性结合并靶向FLCN降解。抑制ATM （ataxia -毛细血管扩张突变）可减弱CSE诱导的FLCN降解，提示ATM在FLCN蛋白水解中的作用。我们进一步证实，FLCN主要磷酸化位点丝氨酸62A的突变体对cse诱导的降解和细胞毒性具有抗性。我们的研究表明，CS暴露是FLCN缺乏的次要原因，因为蛋白质水解增强，从而促进气道上皮细胞死亡。
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. Given that COPD often shares structural features with BHD, we investigated the link between COPD, cigarette smoke (CS) exposure and FLCN expression. 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. 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. Our study demonstrates that CS exposure is a secondary cause of FLCN deficiency due to the enhanced proteolysis, which promoted airway epithelial cell death.
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DOI：
10.4049/jimmunol.1600713
发表时间：
2017-07-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Reyat JS;Chimen M;Noy PJ;Szyroka J;Rainger GE;Tomlinson MG
通讯作者：
Tomlinson MG
DOI：
10.1164/rccm.201505-0999oc
发表时间：
2016-07-15
影响因子：
24.7
作者：
Jiang, Zhiqiang;Lao, Taotao;Zhou, Xiaobo
通讯作者：
Zhou, Xiaobo
DOI：
10.1164/rccm.200802-320oc
发表时间：
2009-02-15
影响因子：
24.7
作者：
Nyunoya, Toru;Monick, Martha M.;Hunninghake, Gary W.
通讯作者：
Hunninghake, Gary W.
影响因子：
2.2
作者：
Gupta, Nishant;Seyama, Kuniaki;McCormack, Francis X.
通讯作者：
McCormack, Francis X.
影响因子：
3.5
作者：
Wang, Lu;Kobayashi, Toshiyuki;Hino, Okio
通讯作者：
Hino, Okio