Over-expression of prothymosin- antagonizes TGF signalling to promote the development of emphysema
Over-expression of prothymosin- antagonizes TGF signalling to promote the development of emphysema
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DOI：
10.1002/path.4664
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发表时间：
2016-02-01
影响因子：
7.3
通讯作者：
Wu, Chao-Liang
中科院分区：
文献类型：
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作者：
Su, Bing-Hua;Tseng, Yau-Lin;Wu, Chao-Liang
肺气肿是慢性阻塞性肺疾病（COPD）的主要后果，其特征在于由肺泡空气空间扩大和肺弹性丧失导致的永久性气流限制。转化生长因子（Transforming growth factor-，TGF）信号传导调节基质金属蛋白酶（matrix metalloproteinase，MMP）/基质金属蛋白酶组织抑制剂（tissue inhibitor of matrix metalloproteinase，TIMP）的平衡以控制基质稳态。COPD患者TGF信号传导失调，通过促炎基因启动子中组蛋白乙酰化的表观遗传上调降低组蛋白去乙酰化酶（HDAC）活性。然而，肺气肿发病机制中HDAC活性降低和TGF信号转导失调之间的潜在联系仍有待确定。胸腺素原（ProT）是一种高度保守的酸性核蛋白，参与组蛋白和非组蛋白的乙酰化。本研究的目的是检验ProT通过Smad 7抑制TGF-Smad信号传导，从而促进肺气肿发病机制的假设。我们发现，ProT增强Smad 7乙酰化，减少其与HDAC的关联，从而下调TGF-Smad信号。ProT通过乙酰化Smad 7促进MMP表达，导致MMP和TIMP之间的失衡。除了干扰R-Smad激活和靶向受体在细胞质中降解外，ProT增强的乙酰化Smad 7竞争性拮抗pSmad 2/3-Smad 4复合物与TIMP-3启动子的结合，导致TIMP-3表达降低。在ProT过表达细胞、显示肺气肿表型的ProT转基因小鼠的肺和肺气肿患者中检测到这些效应。重要的是，在肺气肿患者和香烟烟雾提取物（CSE）诱导的肺气肿小鼠的肺中发现Smad 7增加和TIMP-3减少。这种影响可以通过沉默内源性ProT表达来消除。总的来说，我们的研究结果揭示了乙酰化Smad 7调节的ProT作为一个重要的决定因素，在失调的TGF信号，有助于肺气肿的发病机制。版权所有（c）2015大不列颠和爱尔兰病理学会。由John Wiley & Sons有限公司出版
Emphysema, a major consequence of chronic obstructive pulmonary disease (COPD), is characterized by the permanent airflow restriction resulting from enlargement of alveolar airspace and loss of lung elasticity. Transforming growth factor- (TGF) signalling regulates the balance of matrix metalloproteinase (MMP)/tissue inhibitor of matrix metalloproteinase (TIMP) to control matrix homeostasis. Patients with COPD have dysregulated TGF signalling and reduced histone deacetylase (HDAC) activity through epigenetic up-regulation of histone acetylation in the promoters of pro-inflammatory genes. However, the potential link between decreased HDAC activity and dysregulated TGF signalling in emphysema pathogenesis remains to be determined. Prothymosin (ProT), a highly conserved acidic nuclear protein, plays a role in the acetylation of histone and non-histone proteins. The aim of this study was to test the hypothesis that ProT inhibits TGF-Smad signalling through Smad7, thereby contributing to emphysema pathogenesis. We show that ProT enhances Smad7 acetylation by decreasing its association with HDAC and thereby down-regulates TGF-Smad signalling. ProT caused an imbalance between MMP and TIMP through acetylated Smad7 in favour of MMP expression. In addition to interfering with R-Smad activation and targeting receptors for degradation in the cytoplasm, acetylated Smad7 potentiated by ProT competitively antagonized binding of the pSmad2/3-Smad4 complex to the TIMP-3 promoter, resulting in reduced TIMP-3 expression. These effects were detected in ProT-over-expressing cells, lungs of ProT transgenic mice displaying an emphysema phenotype and in emphysema patients. Importantly, increased Smad7 and reduced TIMP-3 were found in the lungs of emphysema patients and mice with cigarette smoke extract (CSE)-induced emphysema. Such effects could be abrogated by silencing endogenous ProT expression. Collectively, our results uncover acetylated Smad7 regulated by ProT as an important determinant in dysregulated TGF signalling that contributes to emphysema pathogenesis. Copyright (c) 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.