The cGAS-STING Defense Pathway and Its Counteraction by Viruses

Abstract

Upon virus infection, host cells mount a concerted innate immune response involving type I interferon and pro-inflammatory cytokines to enable elimination of the pathogen. Recently, cGAS and STING have been identified as intracellular sensors that activate the interferon pathway in response to virus infection and thus mediate host defense against a range of DNA and RNA viruses. Here we review how viruses are sensed by the cGAS-STING signaling pathway as well as how viruses modulate this pathway. Mechanisms utilized by viral proteins to inhibit cGAS and/or STING are also discussed. On the flip side, host cells have also evolved strategies to thwart viral immune escape. The balance between host immune control and viral immune evasion is pivotal to viral pathogenesis, and we discuss this virus-host stand-off in the context of the cGAS-STING innate immune pathway.

Keywords: IFN; Innate immunity; STING; cGAS; virus.

Figure 1

Pattern Recognition Receptors in Cells Schematic of different pattern recognition receptors in the cell and the signaling pathways that are activated by each PRR. TLRs are either anchored on the cell surface or are present in endosomal compartments. TLRs utilize myeloid differentiation primary response gene 88 (MYD88) or TIR-domain-containing adaptor-inducing interferon (TRIF) as an adaptor protein to recruit downstream molecules, which eventually culminate in the production of pro-inflammatory cytokines and/or type I interferon (IFN). The RLR family is comprised of three receptors, RIG-I, melanoma differentiation-associated gene 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2), each recognizing specific RNA ligands. RLRs signal through the adaptor protein MAVS (also called IPS-1, Cardif, and VISA) located on the mitochondria to trigger the production of type I interferons together with NF-κB. NLRs are cytosolic PRRs that contain a nucleotide-binding domain (NBD), an LRR region, and an N-terminal effector that is typically a caspase activation and recruitment domain (CARD) or a pyrin domain (PYD). Several NLR proteins are members of a large complex called the inflammasome, which includes ASC and procaspase I. Inflammasome induction by a number of different PAMPs, results in the activation of IL-1β and IL-18 from pro-IL-1β and pro-IL-18, respectively. AIM2 is a non-NLR family protein that recognizes cytosolic dsDNA. Similar to NLRs, upon stimulation, AIM2 forms an inflammasome with procaspase I and ASC to induce IL-1β and IL-18.

Figure 2

The cGAS-STING Dependent DNA Sensing Pathway A detailed overview of the cGAS-STING DNA sensing pathway is depicted. Both positive and negative regulators of STING are shown. Black arrows indicate pathways that lead to activation of STING and induction of the type I IFN response. White arrows indicate pathways that negatively regulate STING. Protein ubiquitination is depicted as K48 or K63 linkages, and protein phosphorylation is depicted as P.