Potential Therapeutic Value of the STING Inhibitors

Abstract

The stimulator of interferon genes (STING) is a critical protein in the activation of the immune system in response to DNA. It can participate the inflammatory response process by modulating the inflammation-preferred translation program through the STING-PKR-like endoplasmic reticulum kinase (PERK)-eIF2α pathway or by inducing the secretion of type I interferons (IFNs) and a variety of proinflammatory factors through the recruitment of TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) or the regulation of the nuclear factor kappa-B (NF-κB) pathway. Based on the structure, location, function, genotype, and regulatory mechanism of STING, this review summarizes the potential value of STING inhibitors in the prevention and treatment of infectious diseases, psoriasis, systemic lupus erythematosus, non-alcoholic fatty liver disease, and other inflammatory and autoimmune diseases.

Keywords: STING; disease; genotype; inhibitors; innate immunity; signal transduction.

Figure 1

Cartoon model of the cGAMP-induced oligomerization of wild-type STING.

Figure 2

The structure of hSTING. (A) The hSTING gene map (NCBI reference sequence: NC-000005.10), annotated with common SNPs. (B) Schematic diagram of the hSTING protein domain. Transmembrane domains are marked in blue, common human mutation points are marked in black, regions related to IRF3 activation are marked in green, and SAVI mutation points are marked in red. (C) The crystal structure of the hSTING protein (PDB: 7SII). R232 is marked in red, the HAQ mutation point is marked in blue, and the SAVI mutation point is marked in green. (D) Representation of the STING structure (PDB: 7SII). The secondary protein structure, N-terminus, and C-terminus are numbered. The ER–Golgi membrane is colored in gray.

Figure 3

Schematic diagram of the cGAS-STING signaling pathway. cGAS can recognize abnormally exposed cytoplasmic DNA molecules, including viral and bacterial DNA, DNA produced by the reverse transcription of RNA viruses, and DNA produced by self-cell damage. It can catalyze the synthesis of 2′, 3′-cGAMP, which specifically binds to STING dimer for oligomerization. After activation, STING is translocated to the Golgi via ERGIC, during which TBK1 and IRF3 are recruited, and this complex induces an immune response by phosphorylating IRF3 or NF-κB. In addition, STING can activate PERK and promote the phosphorylation of eIF2α, inducing translation program transformation. Autophagy, ubiquitination, recruitment inhibition, mutation, and other pathways can affect the STING pathway.

Figure 4

STING inhibitors targeting palmitoylation sites.

Figure 5

STING inhibitors targeting CDN binding sites.

Figure 6

STING inhibitor with an unknown site of action.

Figure 7

STING protein degraders.