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

Abstract

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.

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Figure 1: STING is essential for intracellular DNA-mediated type I IFN production.
Figure 2: STING is required for effective in vivo host defence.
Figure 3: STING is required for effective DNA-mediated adaptive immune responses.
Figure 4: STING translocates from the ER to Sec5-containing vesicles.

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Acknowledgements

We thank J. Yewdell for VV-OVA, B. Jacobs for VVΔE3L, K. Frueh for HCMV, M. Kobayashi for baculovirus, H. Horiuchi for the Sec5 antibody, Y. C. Weh for Tbk1-knockout MEFs, and S. Nagata, T. Maniatis, J. Hiscott and N. Reich for plasmid constructs. This work was supported by NIH grant AI079336.

Author Contributions H.I. and G.N.B. designed the research and analysed the data. H.I. performed most experiments. Z.M. performed experiments related to YFV NS4B, carried out exocyst RNAi studies and helped with experiments. G.N.B. wrote the paper.

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Correspondence to Glen N. Barber.

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Ishikawa, H., Ma, Z. & Barber, G. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461, 788–792 (2009). https://doi.org/10.1038/nature08476

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