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

Abstract

As 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 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.