Oxygen enhances antiviral innate immunity through maintenance of EGLN1-catalysed proline hydroxylation of IRF3
Oxygen is essential for aerobic organisms, but little is known about its role in antiviral immunity. Here, we report that during responses to viral infection, the hypoxic conditions repress antiviral-responsive genes independently of HIF signalling. EGLN1 was identified as a key mediator of the enhancement exerted by the oxygen on antiviral innate immune responses. Under sufficient oxygen conditions, EGLN1 maintains its prolyl hydroxylase activity to catalyse hydroxylation of IRF3 at proline 10. This modification enhances IRF3 phosphorylation, dimerisation, and nuclear translocation, leading to subsequent IRF3 activation. Furthermore, mice and zebrafish with Egln1 deletion, treatment with the EGLN inhibitor, FG4592, or mice carrying an Irf3 P10A mutation are more susceptible to viral infections. These findings not only reveal a direct link between oxygen and antiviral responses, but also provide insights into the mechanisms by which oxygen regulates innate immunity Overall design: To investigate the function of the oxygen sensor EGLN1 in innate immune signaling pathways, we constructed wild-type MEF and EGLN1 knockdown MEF cell lines We then performed gene expression analysis in two different cell lines with or without VSV infection by using the data provided by RNA-seq Fastp (version 0.19.7) was used to perform basic statistics on the quality of the raw reads The clean reads were then mapped to the mouse genome using HISAT. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses for the DEGs were performed using Cluster Profiler version 3.8