The N-Terminal Domain of cGAS Determines Preferential Association with Centromeric DNA and Innate Immune Activation in the Nucleus

Cell Rep. 2019 Feb 26;26(9):2377-2393.e13. doi: 10.1016/j.celrep.2019.01.105.


Cytosolic DNA activates cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS), an innate immune sensor pivotal in anti-microbial defense, senescence, auto-immunity, and cancer. cGAS is considered to be a sequence-independent DNA sensor with limited access to nuclear DNA because of compartmentalization. However, the nuclear envelope is a dynamic barrier, and cGAS is present in the nucleus. Here, we identify determinants of nuclear cGAS localization and activation. We show that nuclear-localized cGAS synthesizes cGAMP and induces innate immune activation of dendritic cells, although cGAMP levels are 200-fold lower than following transfection with exogenous DNA. Using cGAS ChIP-seq and a GFP-cGAS knockin mouse, we find nuclear cGAS enrichment on centromeric satellite DNA, confirmed by imaging, and to a lesser extent on LINE elements. The non-enzymatic N-terminal domain of cGAS determines nucleo-cytoplasmic localization, enrichment on centromeres, and activation of nuclear-localized cGAS. These results reveal a preferential functional association of nuclear cGAS with centromeres.

Keywords: IRF3; LINE; STING; cGAMP; cGAS; centromere; dendritic cells; interferon; nuclear envelope; satellite DNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Cell Line
  • Cell Nucleus / enzymology
  • Centromere / enzymology*
  • DNA
  • DNA, Satellite
  • Dendritic Cells / enzymology*
  • Dendritic Cells / immunology*
  • Female
  • HeLa Cells
  • Humans
  • Immunity, Innate / genetics*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nucleotidyltransferases / chemistry
  • Nucleotidyltransferases / metabolism*
  • Protein Domains


  • DNA, Satellite
  • DNA
  • Nucleotidyltransferases
  • cGAS protein, human
  • cGAS protein, mouse