The role of the cGAS-STING signaling pathway in viral infections, inflammatory and autoimmune diseases

Abstract

Pattern recognition receptors are an essential part of the immune system, which detect pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) and help shape both innate and adaptive immune responses. When dsDNA is present, cyclic GMP-AMP Synthase (cGAS) produces a second messenger called cyclic GMP-AMP (cGAMP), which then triggers an adaptor protein called STING, and eventually activates the expression of type I interferon (IFN) and pro-inflammatory cytokines in immune cells. The cGAS-STING signaling pathway has been receiving a lot of attention lately as a key immune-surveillance mediator. In this review, we summarize the present circumstances of the cGAS-STING signaling pathway in viral infections and inflammatory diseases, as well as autoimmune diseases. Modulation of the cGAS-STING signaling pathway provides potential strategies for treating viral infections, inflammatory diseases, and autoimmune diseases.

Keywords: autoimmune diseases; cGAS-STING signaling pathway; double-stranded DNA (dsDNA); inflammatory diseases; type I interferon (IFN); viral infections.

Fig. 1. cGAS-STING and related diseases.

cGAS-STING signaling pathway is correlated to the pathogenesis of SARS-CoV-2 infection, inflammatory bowel disease (IBD), cardiovascular diseases, cancer and autoimmune diseases.

Fig. 2. Structural insights and signal transduction mechanisms of cGAS and STING.

a The structure of cyclic GMP-AMP synthase (cGAS). Human cGAS contains 160 amino with positively charged N terminus and a 360 amino acid C-terminal fragment that includes a nucleotidyltransferase (NTase) core domain (160–330) and the male abnormal 21 (Mab21) domain (213–513). b Schematics of cGAS in nuclear inactive state and in cytoplasmic active state. In the cytoplasm, human cGAS forms dimer to sense cytosolic DNA with DNA-binding surfaces (sites A, B, and C), subsequent in the formation of cGAS-DNA complex and cGAS-DNA liquid phase condensates, to activate the production of the second messenger cyclic GMP-AMP (cGAMP). c The structure of stimulator of interferon genes (STING). Human STING contains N-terminal cytosolic segment, four transmembrane (TM) helices, cyclic-dinucleotide binding domain (CBD), and a C-terminal tail (CTT).

Fig. 3. The cGAS-STING signaling pathway.

DNA binding activates cGAS to generate the second messenger cGAMP, which binds to the stimulator of interferon genes (STING). STING translocates from the ER to the Golgi, where it recruits TANK-binding kinase 1 (TBK1), which phosphorylates interferon regulatory factor 3 (IRF3). Phosphorylated IRF3 dimerizes and translocates to the nucleus to activate type I interferon (IFN).

Fig. 4. SARS-CoV-2 proteins inhibit the cGAS-STING signaling pathway.

SARS-CoV-2 non-structural (3CL-Mpro) and accessory proteins (ORF3α, ORF9b) antagonize innate immune responses by host thereby inhibiting type I interferon (IFN) secretion.

Fig. 5. The dual role of type I interferon (IFN) in COVID-19.

The treatment strategy in the early stage of the COVID-19 disease is to reduce the replication of SARS-CoV-2 virus and promote the production of type I interferon (IFN), and to reduce inflammation as well as inhibit the secretion of type I interferon (IFN) in the later stage of the COVID-19 disease.

Fig. 6. The double edge effect of cGAS-STING signaling pathway in inflammatory bowel disease.

The role of the cGAS-STING signaling pathway in inflammatory bowel disease (IBD) is indeed multifaceted, reflecting double effect with both protective and potentially detrimental.

Fig. 7. Therapeutic targeting of cGAS-STING.

a Mechanisms of action of inhibitors targeting cGAS and STING. b STING agonist restrict virus replication by upregulating type I interferon (IFN) production.