Fig. 1.

A RIG-I-Like receptors (RLRs), such as MDA5 and RIG-I, are activated by numerous cytosolic ligands, such as mitochondrial RNA (mtRNA), 5′-triphosphate RNA, dsRNA, and transposable element transcripts (TEs). cGAS is stimulated in both the cytoplasm and nucleus by several endogenous stimuli, such as micronuclei, mitochondrial DNA (mtDNA), RNA:DNA hybrids, cytosolic chromatin fragments (CCF), naked cytosolic DNA, stalled ribosomes, and most recently RNA. Activation of RLRs promotes oligomerization with the mitochondrial anti-viral signaling protein (MAVS), which triggers activation of kinases like Tank Binding Kinase 1 (TBK1) and IκB kinase ε (IKKε). Stimuli binding to cGAS induces its synthetase activity resulting in production of the second messenger cyclic GMP-AMP (cGAMP). STING activation by cGAMP results in induction of TBK1. Stimulation of either RNA or DNA sensor pathways can ultimately result in the translocation of Interferon Response Factor 3 (IRF3), IRF7, and nuclear factor kappa B (NF-κB) to the nucleus leading to the induction of an IFN response and the secretion of proinflammatory cytokines. Cells possess negative regulators of the sensor pathways including LGP2 and ADAR1 for RLRs and nucleosome tethering and the circular RNA cia-cGAS for nuclear cGAS. B Nucleic acid sensor activation alters stem cell homeostasis in cell-type and context-specific manners. Pathway activation can result in diverse cellular outcomes, such as expansion, exhaustion, senescence, or cell death. Created with BioRender.com