A Chronic Obstructive Pulmonary Disease Susceptibility Gene, FAM13A, Regulates Protein Stability of β-Catenin
A Chronic Obstructive Pulmonary Disease Susceptibility Gene, FAM13A, Regulates Protein Stability of β-Catenin
复制标题
DOI：
10.1164/rccm.201505-0999oc
复制
发表时间：
2016-07-15
影响因子：
24.7
通讯作者：
Zhou, Xiaobo
中科院分区：
文献类型：
--
作者：
Jiang, Zhiqiang;Lao, Taotao;Zhou, Xiaobo
基本原理：在全基因组关联研究中，FAM 13 A基因内的遗传位点一直与慢性阻塞性肺疾病（COPD）相关。目的：研究FAM 13 A在人COPD和小鼠COPD模型中的生物学功能，探讨FAM 13 A影响COPD易感性的分子机制。在Fam 13 a（-/-）和Fam 13 a（+/+）同窝对照小鼠中评估肺部炎症反应和空域大小。分别采用免疫荧光法、Western印迹法和逆转录聚合酶链反应法检测COPD肺组织中FAM 13 A蛋白的细胞定位和FAM 13 A mRNA水平。免疫沉淀，然后质谱鉴定细胞蛋白质与FAM 13 A相互作用，揭示FAM 13 A的function. Measures和主要结果：在小鼠和人的肺，FAM 13 A表达在气道和肺泡II型上皮细胞和巨噬细胞。与Fam 13 a（+/+）小鼠相比，Fam 13 a敲除小鼠（Fam 13 a（-/-））对慢性香烟烟雾诱导的肺气肿具有抗性。在体外，FAM 13 A与蛋白磷酸酶2A相互作用，并与糖原合成酶激酶3 β和β-连环蛋白一起募集蛋白磷酸酶2A，诱导β-连环蛋白降解。Fam 13 a（-/-）小鼠也对弹性蛋白酶诱导的肺气肿具有抗性，并且这种抗性通过共同施用β-连环蛋白抑制剂而逆转，这表明FAM 13 A可以通过抑制β-连环蛋白信号传导来增加小鼠对肺气肿发展的易感性。结论：FAM 13 A可能通过促进β-catenin降解而影响COPD易感性。
Rationale: A genetic locus within the FAM13A gene has been consistently associated with chronic obstructive pulmonary disease (COPD) in genome-wide association studies. However, the mechanisms by which FAM13A contributes to COPD susceptibility are unknown.Objectives: To determine the biologic function of FAM13A in human COPD and murine COPD models and discover the molecular mechanism by which FAM13A influences COPD susceptibility.Methods: Fam13a null mice (Fam13a(-/-)) were generated and exposed to cigarette smoke. The lung inflammatory response and airspace size were assessed in Fam13a(-/-) and Fam13a(+/+) littermate control mice. Cellular localization of FAM13A protein and mRNA levels of FAM13A in COPD lungs were assessed using immunofluorescence, Western blotting, and reverse transcriptase-polymerase chain reaction, respectively. Immunoprecipitation followed by mass spectrometry identified cellular proteins that interact with FAM13A to reveal insights on FAM13A's function.Measurements and Main Results: In murine and human lungs, FAM13A is expressed in airway and alveolar type II epithelial cells and macrophages. Fam13a null mice (Fam13a(-/-)) were resistant to chronic cigarette smoke-induced emphysema compared with Fam13a(+/+) mice. In vitro, FAM13A interacts with protein phosphatase 2A and recruits protein phosphatase 2A with glycogen synthase kinase 3 beta and beta-catenin, inducing beta-catenin degradation. Fam13a(-/-) mice were also resistant to elastase-induced emphysema, and this resistance was reversed by coadministration of a beta-catenin inhibitor, suggesting that FAM13A could increase the susceptibility of mice to emphysema development by inhibiting b-catenin signaling. Moreover, human COPD lungs had decreased protein levels of beta-catenin and increased protein levels of FAM13A.Conclusions: We show that FAM13A may influence COPD susceptibility by promoting b-catenin degradation.