cGAS and STING: At the intersection of DNA and RNA virus-sensing networks

Innate immune sensing of RNA and DNA virusesAs the first line of host defense, the innate immune system utilizes germline-encoded receptors named pattern-recognition receptors (PRRs) to detect invading pathogens.PRRs recognize conserved molecular structures of pathogens known as pathogen-associated molecular patterns (PAMPs) to initiate immune responses that counteract pathogen infection.The immunostimulatory feature of exogenous nucleic acids, such as viral DNA and RNA, has been known for more than half a century, but the mechanism by which they function as an immune stimulant remained unclear for a long time.The past two decades have witnessed tremendous progress in understanding the signaling mechanisms of innate immune networks and established the retinoic acid inducible gene-I (RIG-I)/melanoma differentiation associated gene 5 (MDA5)-mitochondrial antiviral-signaling protein (MAVS) axis and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) axis as the major sensing pathways for cytosolic RNA and DNA, respectively [1].However, emerging evidence indicates that, in addition to its well-established role in sensing cytosolic DNA, the cGAS-STING pathway is also involved in restricting RNA virus infection, suggesting that there exists crosstalk between the innate sensing of cytosolic DNA and RNA. Canonical role of the cGAS-STING pathway in sensing DNA virus infectioncGAS binds to cytosolic double-stranded DNA (dsDNA) from various sources, including bacteria, DNA viruses, and retroviruses, in a sequence-independent but length-dependent manner [1,2].Following the binding of dsDNA, cGAS catalyzes the production of a second messenger known as cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) in the presence of GTP and ATP, which subsequently binds to the adaptor protein STING on the endoplasmic reticulum (ER) membrane [1].Aside from cGAMP, STING also directly senses other cyclic dinucleotides (CDNs), which are secreted by some bacteria [3].After binding to CDNs, the STING dimer undergoes a dramatic trafficking process from the ER to the Golgi complex and eventually to perinuclear compartments to form large punctate structures where it is degraded [4].STING recruits TANK binding kinase 1 (TBK1) and activates transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor-κB (NF-κB), which then translocate into the nucleus to induce the transcriptional activation of type I interferons (IFNs) and other inflammatory cytokines, thus establishing an antiviral state in infected and uninfected neighboring host cells [4] (Fig 1).Numerous DNA viruses have been reported to activate the cGAS-STING pathway, and cGAS or STING deficient mice are more susceptible to lethal infection after exposure to many DNA viruses, including herpes