A novel transcript isoform of STING that sequesters cGAMP and dominantly inhibits innate nucleic acid sensing

Abstract

STING is a core adaptor in innate nucleic acid sensing in mammalian cells, on which different sensing pathways converge to induce type I interferon (IFN) production. Particularly, STING is activated by 2′3′-cGAMP, a cyclic dinucleotide containing mixed phosphodiester linkages and produced by cytoplasmic DNA sensor cGAS. Here, we reported on a novel transcript isoform of STING designated STING-β that dominantly inhibits innate nucleic acid sensing. STING-β without transmembrane domains was widely expressed at low levels in various human tissues and viral induction of STING-β correlated inversely with IFN-β production. The expression of STING-β declined in patients with lupus, in which type I IFNs are commonly overproduced. STING-β suppressed the induction of IFNs, IFN-stimulated genes and other cytokines by various immunostimulatory agents including cyclic dinucleotides, DNA, RNA and viruses, whereas depletion of STING-β showed the opposite effect. STING-β interacted with STING-α and antagonized its antiviral function. STING-β also interacted with TBK1 and prevented it from binding with STING-α, TRIF or other transducers. In addition, STING-β bound to 2′3′-cGAMP and impeded its binding with and activation of STING-α, leading to suppression of IFN-β production. Taken together, STING-β sequesters 2′3′-cGAMP second messenger and other transducer molecules to inhibit innate nucleic acid sensing dominantly.

Inhibition of AIM 2 inflammasome activation by a novel transcript isoform of IFI 16

“…Consistent with the binding between IFI16-b and STING, IFI16-b colocalized with STING in HeLa cells and the co-localization was even more pronounced when cGAS was also overexpressed ( Fig 4E). Notably, the discrete punctate staining pattern of STING in the cytoplasm of these cells was compatible with the notion that aggregate formation was required for its activation [44][45][46]. Thus, IFI16-b interacts with and activates STING for type I IFN production.…”

STING pathway agonism as a cancer therapeutic

“…It does so by sequestering STING as well as cGAMP, TBK1, and other signaling components. Notably, STING‐β expression anticorrelates with type I IFN production, and may rapidly release STING pathway components following stress or infection . A third isoform, MITA‐related protein (MRP), inhibits IRF3 activation but is capable of activating NF‐κB .…”

“…Notably, STING-β expression anticorrelates with type I IFN production, and may rapidly release STING pathway components following stress or infection. 54 A third isoform, MITA-related protein (MRP), inhibits IRF3 activation but is capable of activating NF-κB. 55 Thus, drugs designed to inhibit the regulatory isoforms may allow the stimulatory isoforms to carry out downstream signaling more successfully.…”

Increasing Host Cellular Receptor—Angiotensin-Converting Enzyme 2 (ACE2) Expression by Coronavirus may Facilitate 2019-nCoV Infection

“…Here we analyzed the various microarray database of virus infected-or inflammatory stimulated-animals and cells, and clearly show that virus infection including SARS-CoV and MERS-CoV can obviously upregulate ACE2 expression, which suggests that 2019-nCoV may use similar strategies to augment its infection and spread. Plasmids pcDNA6B-TBK1-FLAG and pcDNA6B-TRIF-FLAG were constructed using standard molecular cloning methods as described previously (Wang et al, 2018).…”