IFI16 is required for DNA sensing in human macrophages by promoting production and function of cGAMP

Nat Commun. 2017 Feb 10;8:14391. doi: 10.1038/ncomms14391.

Abstract

Innate immune activation by macrophages is an essential part of host defence against infection. Cytosolic recognition of microbial DNA in macrophages leads to induction of interferons and cytokines through activation of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Other host factors, including interferon-gamma inducible factor 16 (IFI16), have been proposed to contribute to immune activation by DNA. However, their relation to the cGAS-STING pathway is not clear. Here, we show that IFI16 functions in the cGAS-STING pathway on two distinct levels. Depletion of IFI16 in macrophages impairs cGAMP production on DNA stimulation, whereas overexpression of IFI16 amplifies the function of cGAS. Furthermore, IFI16 is vital for the downstream signalling stimulated by cGAMP, facilitating recruitment and activation of TANK-binding kinase 1 in STING complex. Collectively, our results suggest that IFI16 is essential for efficient sensing and signalling upon DNA challenge in macrophages to promote interferons and antiviral responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • DNA / metabolism*
  • Gene Expression Profiling
  • HEK293 Cells
  • Humans
  • Immunity, Innate / genetics
  • Interferons / immunology
  • Interferons / metabolism
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Macrophages / virology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mutation
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Nucleotides, Cyclic / metabolism*
  • Nucleotidyltransferases / genetics
  • Nucleotidyltransferases / metabolism
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • RNA Interference
  • Signal Transduction / genetics
  • THP-1 Cells

Substances

  • Membrane Proteins
  • Nuclear Proteins
  • Nucleotides, Cyclic
  • Phosphoproteins
  • STING1 protein, human
  • cyclic guanosine monophosphate-adenosine monophosphate
  • IFI16 protein, human
  • DNA
  • Interferons
  • Protein Serine-Threonine Kinases
  • TBK1 protein, human
  • Nucleotidyltransferases
  • cGAS protein, human