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

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. •STING and ORMDL3 genes expression was increased in patients with recurrent wheeze.•STING upregulates ORMDL3 expression and promoter activity in cells.•ORMDL3 is positively associated with the STING-TBK1-IRF3/STAT6 signaling pathway.•STING increases the ORMDL3 expression in asthma and recurrent wheeze by promoting both the expression and activity of the TBK1-IRF3-STAT6 complex.