Uncovering novel suppressors of endogenous nucleic acid ligands

Abstract

Type I interferons (IFNs) are important for controlling viral infections, but aberrant IFN expression can result in tissue damage. IFNs are induced following activation of pattern recognition receptors that sense pathogen associated DNA and RNA. RIG-I-like receptors (RLRs), RIG-I and MDA5, sense viral RNA and signal through the adaptor protein MAVS, while cGAS and DDX41 sense viral DNA signal though the adaptor protein STING. Activation of MAVS or STING leads to the phosphorylation and nuclear translocation of the transcription factor IRF3, in turn inducing IFNs. While activation of these pathways is often driven by viral nucleic acids, both pathways can be activated by host endogenous nucleic acids. Therefore, several mechanisms exist to prevent recognition of host nucleic acids by these receptors in order to prevent aberrant expression of IFN and IFN-mediated disease. Identifying factors important for suppressing endogenous DNA and RNA ligands is critical for preventing IFN-induced autoimmunity. In this dissertation, we identify two novel regulators that suppresses endogenous nucleic acids that activate the RLR pathway or the cGAS/DDX41/STING pathway. We discovered that the transcription factor MEF2A is required to suppresses the accumulation of RNA:DNA hybrids and DNA-damage which leads to the unscheduled activation of STING and production of IFN. Interestingly, STING activation required cGAS and DDX41 demonstrating a previously undescribed role for DDX41 driven activation of STING through genomic RNA:DNA hybrids. We also uncovered a novel role for the splicing factor CELF2 as a suppressor of endogenous RNA ligands. Depletion of CELF2 in monocytes leads to a spontaneous IFN and IFN-stimulated gene signature, dependent on the RIG-I-MAVS pathway. These data are the first to demonstrate a role for MEF2A and CELF2 in suppressing endogenous nucleic acid ligands, which can activate host pattern recognition receptors to induce an IFN signature. Overall, these findings suggest that MEF2A and CELF2 are important for preventing IFN-induced inflammation.