Background
Autoinflammatory disorders are a group of conditions that are caused by dysregulation of the innate immune system. Genetic mutation of the alpha subunit in coatomer complex I (COPA), is known to cause an inherited inflammatory disorder. In a COPA deficient cell model, our lab has identified spontaneous activated the cGAS/STING pathway and increased type I IFN signalling. In a similar model with genetic deletion of other coatomer complex I subunits, we found that in cells lacking COPG1, type I IFN activation was also induced, suggesting that mutations in COPG1 could also cause inflammatory diseases. A patient with COPG1 mutation and clinical inflammatory phenotypes was identified, further suggesting that mutation in COPG1 could be the cause of a novel inflammatory disorder.
Method/Result
We first generated a COPG1 deleted cell model by CRISPR/Cas9 editing. We have identified increased type I IFN signalling in COPG1 deleted cells at both transcriptional and translational level, triggering activation of downstream interferon stimulated genes and increased phosphorylation of signalling molecule, STAT1. Next, we treated the COPG1 knockout cells with STING inhibitor H151 in a 15-hour time window. We found that the phenotypic increase in phosphorylation of STAT1 was ameliorated with a dose response to H151. In the future, we will induce expression of the COPG1 patient mutation in this model and further study what role does cGAS/STING pathway play in the patients disease.
Conclusion
This study identifies enhanced inflammatory phenotypes due to deletion of COPG1 and provides insights into a potential inflammatory disorder caused by a loss of function COPG1 mutation.