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-? that dominantly inhibits innate nucleic acid sensing. STING-? without transmembrane domains was widely expressed at low levels in various human tissues and viral induction of STING-? correlated inversely with IFN-? production. The expression of STING-? declined in patients with lupus, in which type I IFNs are commonly overproduced. STING-? 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-? showed the opposite effect. STING-? interacted with STING-? and antagonized its antiviral function. STING-? also interacted with TBK1 and prevented it from binding with STING-?, TRIF or other transducers. In addition, STING-? bound to 2'3'-cGAMP and impeded its binding with and activation of STING-?, leading to suppression of IFN-? production. Taken together, STING-? sequesters 2'3'-cGAMP second messenger and other transducer molecules to inhibit innate nucleic acid sensing dominantly.

SUBMITTER: Wang PH 

PROVIDER: S-EPMC5934658 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature