STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity

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Abstract
The adaptor protein STING ('stimulator of interferon genes', also known as MITA and ERIS) is emerging as an important component of the innate immune system's response to microbial DNA. Ishikawa et al. show that in the absence of STING the sensitivity of mice to infection by several DNA and RNA viruses is enhanced. STING-mediated interferon induction requires STING to relocalize with TANK-binding kinase 1 from the endoplasmic reticulum to Sec5-containing endosome vesicles. This work implies that STING is essential for host defence against DNA pathogens such as herpes simplex virus. Although the innate immune system is known to be critical for the early detection of invading pathogens and for initiating host defence systems, little is known about how it is galvanized to respond to DNA-based microbes. STING (stimulator of interferon genes) is now shown to be necessary for the initiation of effective type I interferon production and, accordingly, there is an increase in the susceptibility of Sting-knockout mice to infection by the DNA virus HSV-1. The innate immune system is critical for the early detection of invading pathogens and for initiating cellular host defence countermeasures, which include the production of type I interferon (IFN)1,2,3. However, little is known about how the innate immune system is galvanized to respond to DNA-based microbes. Here we show that STING (stimulator of interferon genes) is critical for the induction of IFN by non-CpG intracellular DNA species produced by various DNA pathogens after infection4. Murine embryonic fibroblasts, as well as antigen presenting cells such as macrophages and dendritic cells (exposed to intracellular B-form DNA, the DNA virus herpes simplex virus 1 (HSV-1) or bacteria Listeria monocytogenes), were found to require STING to initiate effective IFN production. Accordingly, Sting-knockout mice were susceptible to lethal infection after exposure to HSV-1. The importance of STING in facilitating DNA-mediated innate immune responses was further evident because cytotoxic T-cell responses induced by plasmid DNA vaccination were reduced in Sting-deficient animals. In the presence of intracellular DNA, STING relocalized with TANK-binding kinase 1 (TBK1) from the endoplasmic reticulum to perinuclear vesicles containing the exocyst component Sec5 (also known as EXOC2). Collectively, our studies indicate that STING is essential for host defence against DNA pathogens such as HSV-1 and facilitates the adjuvant activity of DNA-based vaccines.