Small-molecule perturbation profiling reveals a mechanistic link between STING signaling and lipid metabolism in...

The DNA sensor cGAS and the signaling adaptor STING play a key role in the innate immune response to microbial and endogenous DNA in the cytoplasm. The cGAS-STING signaling pathway has evolved to promote immune defense and organismal fitness, yet its dysregulation can lead to chronic inflammation, autoimmunity, and neurodegeneration. Upon sensing double-stranded DNA, cGAS produces a cyclic dinucleotide second messenger that binds to STING in the endoplasmic reticulum. Ligand-bound STING translocates to the Golgi and activates a signaling cascade that results in interferon (IFN) gene transcription. These molecular events are mechanistically linked to intracellular lipid membrane dynamics and protein lipidation. To explore whether STING signaling is controlled by the availability and metabolic flux of cellular lipids, we screened small-molecule compounds targeting lipid metabolic pathways for their influence on STING agonist-responsive IFN induction. These screens identified inhibitors of the fatty acid synthase FAS and lipases as potent suppressors of STING signaling. An inhibitor of the cholesterol-esterifying enzyme SOAT1 enhanced STING-dependent IFN induction in mouse cells while attenuating it in human cells. From an analysis of STING sequences, we detected a difference in their lipid binding motifs that likely accounted for the species-specific effects of SOAT1 inhibition. Our findings reveal a connection between STING signaling and lipid metabolism and opportunities for expanding the toolbox for treating clinical conditions that arise from aberrant STING activity.