Proteasome dysfunction inhibits surfactant protein gene expression in lung epithelial cells: mechanism of inhibition of SP-B gene expression
Proteasome dysfunction inhibits surfactant protein gene expression in lung epithelial cells: mechanism of inhibition of SP-B gene expression
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DOI：
10.1152/ajplung.00103.2006
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发表时间：
2007-01-01
影响因子：
4.9
通讯作者：
Boggaram, Vijayakumar
中科院分区：
文献类型：
--
作者：
Das, Aparajita;Boggaram, Vijayakumar
表面活性剂蛋白通过其降低肺泡表面张力和控制肺中的先天免疫应答的作用来维持肺功能。泛素蛋白酶体途径负责真核细胞中大多数细胞内蛋白的降解，并且蛋白酶体功能障碍与神经退行性疾病、心脏病和其他疾病的发展有关。间质性肺疾病中蛋白酶体功能受损与表面活性蛋白C（SP-C）突变映射到位于proSP-C蛋白的BRICHOS结构域相关。在这项研究中，我们确定了蛋白酶体抑制对H441和MLE-12肺上皮细胞表面活性蛋白表达的影响，以了解蛋白酶体功能障碍与表面活性蛋白基因表达之间的关系。蛋白酶体抑制剂lactacystin和MG 132以浓度依赖性方式降低H441和MLE-12细胞中SP-A、SP-B和SP-C mRNA的水平。在H441细胞中，lactacystin和MG 132对SP-B mRNA的抑制与SP-B蛋白的类似降低相关，并且抑制是由于基因转录的抑制。蛋白酶体抑制剂降低甲状腺转录因子-1（TTF-1）/Nkx2.1 DNA结合活性，并且TTF-1 DNA结合活性的降低是由于TTF-1蛋白表达水平的降低。这些数据表明，泛素蛋白酶体途径是维持表面活性蛋白基因表达所必需的，并且该途径的破坏通过减少TTF-1蛋白的表达来抑制表面活性蛋白基因表达。
Surfactant proteins maintain lung function through their actions to reduce alveolar surface tension and control of innate immune responses in the lung. The ubiquitin proteasome pathway is responsible for the degradation of majority of intracellular proteins in eukaryotic cells, and proteasome dysfunction has been linked to the development of neurodegenerative, cardiac, and other diseases. Proteasome function is impaired in interstitial lung diseases associated with surfactant protein C (SP-C) mutation mapping to the BRICHOS domain located in the proSP-C protein. In this study we determined the effects of proteasome inhibition on surfactant protein expression in H441 and MLE-12 lung epithelial cells to understand the relationship between proteasome dysfunction and surfactant protein gene expression. Proteasome inhibitors lactacystin and MG132 reduced the levels of SP-A, SP-B, and SP-C mRNAs in a concentration-dependent manner in H441 and MLE-12 cells. In H441 cells, lactacystin and MG132 inhibition of SP-B mRNA was associated with similar decreases in SP-B protein, and the inhibition was due to inhibition of gene transcription. Proteasome inhibitors decreased thyroid transcription factor-1 (TTF-1)/Nkx2.1 DNA binding activity, and the reduced TTF-1 DNA binding activity was due to reduced expression levels of TTF-1 protein. These data indicated that the ubiquitin proteasome pathway is essential for the maintenance of surfactant protein gene expression and that disruption of this pathway inhibits surfactant protein gene expression via reduced expression of TTF-1 protein.