STING 通过 TBK1-IRF3-STAT6 复合物介导正向调节人 ORMDL3 的表达。

STING positively regulates human ORMDL3 expression through TBK1-IRF3-STAT6 complex mediation.

机构信息

Department of Pediatrics, The First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.

The First Clinical Medical School, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.

出版信息

Exp Cell Res. 2018 Sep 15;370(2):498-505. doi: 10.1016/j.yexcr.2018.07.015. Epub 2018 Aug 1.

DOI:10.1016/j.yexcr.2018.07.015

PMID:30009792

Abstract

Orosomucoid 1-like protein 3 (ORMDL3) is an asthma candidate gene associated with virus-triggered recurrent wheeze. Stimulator of interferon gene (STING) controls TLR-independent cytosolic responses to viruses. However, the association of STING with ORMDL3 is unclear. Here, we have shown that ORMDL3 expression shows a linear correlation with STING in recurrent wheeze patients. In elucidating the molecular mechanisms of the ORMDL3-STING relationship, we found that STING promoted the transcriptional activity of ORMDL3, which was significantly associated with increased levels of interferon regulatory factor 3 (IRF3) and signal transducer and activator of transcription 6 (STAT6). Further study showed that via activation of TANK binding kinase 1 (TBK1), STING enhanced the phosphorylation and binding of IRF3 and STAT6, which upregulated ORMDL3 by binding to the promoter. Our results showed that STING positively regulated ORMDL3 through the TBK1-IRF3-STAT6 complex.

摘要

载脂蛋白样蛋白 3（ORMDL3）是一种与病毒触发复发性喘息相关的哮喘候选基因。干扰素基因刺激物（STING）控制 TLR 非依赖性细胞溶质对病毒的反应。然而，STING 与 ORMDL3 的关联尚不清楚。在这里，我们已经表明，复发性喘息患者的 ORMDL3 表达与 STING 呈线性相关。在阐明 ORMDL3-STING 关系的分子机制时，我们发现 STING 促进了 ORMDL3 的转录活性，这与干扰素调节因子 3（IRF3）和信号转导和转录激活因子 6（STAT6）水平的增加显著相关。进一步的研究表明，通过激活 TANK 结合激酶 1（TBK1），STING 增强了 IRF3 和 STAT6 的磷酸化和结合，通过与启动子结合而上调 ORMDL3。我们的研究结果表明，STING 通过 TBK1-IRF3-STAT6 复合物正向调节 ORMDL3。