Research ArticleInnate Immunity

PKR-dependent cytosolic cGAS foci are necessary for intracellular DNA sensing

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Science Signaling  26 Nov 2019:
Vol. 12, Issue 609, eaav7934
DOI: 10.1126/scisignal.aav7934

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Aberrant intracellular recognition of self-DNA is controlled by the spatial restriction of the DNA sensor cGAS. To define the interactions that may control cGAS subcellular localization, Hu et al. used mass spectrometry and immunoprecipitation to confirm that endogenous cGAS bound to the nucleotide helicase G3BP1, which is involved in stress granule formation. After DNA stimulation of human cells, cGAS associated in an RNA-dependent manner with G3BP1 and was found in cytoplasmic foci that also contained mRNA and the RNA-dependent kinase PKR. Formation of cytoplasmic cGAS condensates necessary for DNA-stimulated type I interferon production required G3BP1 and PKR activity. Together, these data suggest that G3BP1 cytoplasmic foci act as hubs that may coordinate DNA and RNA nucleic acid sensing.

Abstract

Cyclic GMP-AMP synthase (cGAS) is a major sensor of cytosolic DNA from invading pathogens and damaged cellular organelles. Activation of cGAS promotes liquid-like phase separation and formation of membraneless cytoplasmic structures. Here, we found that cGAS bound G3BP1, a double-stranded nucleic acid helicase involved in the formation of stress granules. Loss of G3BP1 blocked subcellular cGAS condensation and suppressed the interferon response to intracellular DNA and DNA virus particles in cells. Furthermore, an RNA-dependent association with PKR promoted G3BP1 foci formation and cGAS-dependent interferon responses. Together, these results indicate that PKR promotes the formation of G3BP1-dependent, membraneless cytoplasmic structures necessary for the DNA-sensing function of cGAS in human cells. These data suggest that there is a previously unappreciated link between nucleic acid sensing pathways, which requires the formation of specialized subcellular structures.

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