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

作者：Wang Pei Hui; Fung Sin Yee; Gao Wei Wei; Deng Jian Jun; Cheng Yun; Chaudhary Vidyanath; Yuen Kit San; Ho Ting Hin; Chan Ching Ping; Zhang Yan; Kok Kin Hang; Yang Wanling; Chan Chi Ping; Jin Dong Yan^*

来源：Nucleic Acids Research, 2018, 46(8): 4054-4071.

DOI：10.1093/nar/gkyl86

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

• 出版日期2018-5-4
• 单位香港大学