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

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

Author information

1
Immunity and Cancer Department, Institut Curie, PSL Research University, INSERM U932, 75005 Paris, France.
2
Institut Curie, PSL Research University, CNRS, UMR 144, 75005 Paris, France; Institut Pierre-Gilles de Gennes, PSL Research University, 75005 Paris, France.
3
Institut Curie, PSL Research University, Sorbonne Universités, CNRS, UMR 3244 Telomere and Cancer Lab, 75005 Paris, France.
4
Institut Curie, PSL Research University, CNRS, UMR 144, 75005 Paris, France.
5
Immunity and Cancer Department, Institut Curie, PSL Research University, INSERM U932, 75005 Paris, France. Electronic address: nicolas.manel@curie.fr.

Abstract

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

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