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

Cell Reports
Matteo GentiliNicolas Manel

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.

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Datasets Mentioned

BETA
GM12878
SRR633615
GSE29611
GSE31755
GSE125475

Methods Mentioned

BETA
nuclear translocation
Confocal microscopy
ELISA
transfection
nuclear
immunoprecipitation
ChIP-seq
ChIP
PCR
PMA

Software Mentioned

samtools
POWERPLEX
GraphPad
Prism
Bowtie2
MetaMorph
bedtools
Huygens Essentials
house
gemtools

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