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

Nature. 2009 Oct 8;461(7265):788-92. doi: 10.1038/nature08476. Epub 2009 Sep 23.

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). 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 infection. 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigen-Presenting Cells / immunology
  • Antigen-Presenting Cells / metabolism
  • Antigen-Presenting Cells / microbiology
  • Antigen-Presenting Cells / virology
  • Cytoplasmic Vesicles / metabolism
  • DNA, Bacterial / immunology*
  • DNA, Bacterial / metabolism
  • DNA, Viral / immunology*
  • DNA, Viral / metabolism
  • Endoplasmic Reticulum / metabolism
  • Fibroblasts / immunology
  • Fibroblasts / metabolism
  • Fibroblasts / microbiology
  • Fibroblasts / virology
  • Herpesvirus 1, Human / genetics
  • Herpesvirus 1, Human / immunology
  • Herpesvirus 1, Human / pathogenicity
  • Immunity, Innate / immunology*
  • Interferon Type I / biosynthesis
  • Interferon Type I / immunology*
  • Intracellular Space / immunology
  • Intracellular Space / metabolism*
  • Listeria monocytogenes / genetics
  • Listeria monocytogenes / immunology
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Plasmids / genetics
  • Plasmids / immunology
  • Protein Transport
  • Protein-Serine-Threonine Kinases / metabolism
  • T-Lymphocytes, Cytotoxic / immunology
  • Vaccines, DNA / immunology
  • Vesicular Transport Proteins / metabolism

Substances

  • DNA, Bacterial
  • DNA, Viral
  • Exoc2 protein, mouse
  • Interferon Type I
  • Membrane Proteins
  • Sting1 protein, mouse
  • Vaccines, DNA
  • Vesicular Transport Proteins
  • Tbk1 protein, mouse
  • Protein-Serine-Threonine Kinases