When STING Meets Viruses: Sensing, Trafficking and Response

Abstract

To effectively defend against microbial pathogens, the host cells mount antiviral innate immune responses by producing interferons (IFNs), and hundreds of IFN-stimulated genes (ISGs). Upon recognition of cytoplasmic viral or bacterial DNAs and abnormal endogenous DNAs, the DNA sensor cGAS synthesizes 2',3'-cGAMP that induces STING (stimulator of interferon genes) undergoing conformational changes, cellular trafficking, and the activation of downstream factors. Therefore, STING plays a pivotal role in preventing microbial pathogen infection by sensing DNAs during pathogen invasion. This review is dedicated to the recent advances in the dynamic regulations of STING activation, intracellular trafficking, and post-translational modifications (PTMs) by the host and microbial proteins.

Keywords: DNA viruses; STING; cellular trafficking; immune responses; post translational modifications.

FIGURE 1

Diagram of STING-mediated immune response to viruses. The cytosolic dsDNA derived from DNA viruses, bacteria CDNs and mitochondria are sensed by cGAS, which catalyzes ATP and GTP to generate cGAMP. Cyclic GAMP directly binds to the pocket of STING dimer and initiates the translocation of STING. STING translocates from the ER to ERGIC, Golgi apparatus and endosome, where it is degraded in the lysosome. The phosphorylation, ubiquitination, and palmitoylation are essential for the activation of STING. The activated STING dimer recruits TBK1 to form the translocation complex. By recruiting and phosphorylating IRF3, the complex promoted IRF3 to entry into nucleus. STING induces the expression of type I IFN genes and other pro-inflammatory cytokines through the TBK1–IRF3 axis and NF-κB signal pathway.

FIGURE 2

The process and regulation of STING trafficking. After stimulated by cytosolic dsDNA, STING dimer exist from the ER to ERGIC, Golgi, and endosomes. The process of trafficking is mediated by diverse proteins. The thick black arrows indicate the pathway that lead to activation and trafficking of STING. The thin black arrows indicate the regulators which positively regulates the trafficking of STING. The white arrows indicate the regulators which negatively regulates the trafficking of STING. Full name of the abbreviations: VPS34 (Vacuolar protein sorting-associated protein 34); SNX8 (Sorting nexin-8); YIPF5 (Yip1 Domain Family Member 5); MTMR3/4 (Myotubularin Related Protein 3); TRAPβ (Translocon-associated protein β); Sec61β (SEC61 Translocon Subunit Beta); iRhom2 (inactive rhomboid 2); ATG9A (Autophagy-related protein 9A); and Cop II (Coat protein II).