Evolutionary conservation analysis reveals a primordial function of STING as a regulator of lipid metabolism via FADS2

Abstract

The stimulator of interferon genes (STING) is a pivotal regulator of type I interferon (IFN) responses. Although the IFN system is confined to vertebrates, STING is present across metazoans and in some unicellular eukaryotes, suggesting involvement in distinct functions prior to vertebrate divergence. Here we explore the conservation of STING-mediated regulation of polyunsaturated fatty acid (PUFA) metabolism. We find that STING homologs from vertebrates, invertebrates, and unicellular eukaryotes interact with fatty acid desaturase 2 (FADS2), the rate-limiting enzyme in PUFA metabolism, and influence subsequent functional outputs. Specifically, we show that STING homologs differentially shape cell susceptibility to infection by DNA and RNA viruses independently of the activation of IFN responses, suggesting that STING-mediated metabolic pathway regulation may participate in primitive host defense mechanisms. Thus, we identify STING-mediated metabolic regulation as an evolutionarily conserved feature and a primordial function of STING. STING is a well-known activator of type I interferon (IFN-I) responses. However, it is debated whether STING has an ancestral function independent of interferon responses. Here, by combining evolutionary comparative analysis and lipidomics, the authors show that STING homologs regulate polyunsaturated fatty acid (PUFA) metabolism via FADS2 and that this primordial STING-mediated metabolic control regulates responses to viral infections independently of antiviral IFN-I signaling.