Manganese Increases the Sensitivity of the cGAS-STING Pathway for Double-Stranded DNA and Is Required for the Host Defense against DNA Viruses

Immunity. 2018 Apr 17;48(4):675-687.e7. doi: 10.1016/j.immuni.2018.03.017. Epub 2018 Apr 10.


Manganese (Mn) is essential for many physiological processes, but its functions in innate immunity remain undefined. Here, we found that Mn2+ was required for the host defense against DNA viruses by increasing the sensitivity of the DNA sensor cGAS and its downstream adaptor protein STING. Mn2+ was released from membrane-enclosed organelles upon viral infection and accumulated in the cytosol where it bound directly to cGAS. Mn2+ enhanced the sensitivity of cGAS to double-stranded DNA (dsDNA) and its enzymatic activity, enabling cGAS to produce secondary messenger cGAMP in the presence of low concentrations of dsDNA that would otherwise be non-stimulatory. Mn2+ also enhanced STING activity by augmenting cGAMP-STING binding affinity. Mn-deficient mice showed diminished cytokine production and were more vulnerable to DNA viruses, and Mn-deficient STING-deficient mice showed no increased susceptibility. These findings indicate that Mn is critically involved and required for the host defense against DNA viruses.

Keywords: Innate immunity; Manganese; STING; cGAS; interferons; virus infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Cell Line
  • Cricetinae
  • DNA Virus Infections / immunology*
  • DNA Viruses / immunology*
  • DNA, Viral / immunology*
  • Enzyme Activation / immunology
  • Female
  • HEK293 Cells
  • HeLa Cells
  • Host-Pathogen Interactions
  • Humans
  • Immunity, Innate / immunology
  • Male
  • Manganese / metabolism*
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Nucleotidyltransferases / metabolism*
  • Young Adult


  • DNA, Viral
  • Membrane Proteins
  • STING1 protein, human
  • Manganese
  • Nucleotidyltransferases
  • cGAS protein, human