期刊
CELL REPORTS
卷 26, 期 9, 页码 2377-+出版社
CELL PRESS
DOI: 10.1016/j.celrep.2019.01.105
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资金
- LABEX VRI [ANR-10-LABX-77]
- LABEX DCBIOL [ANR-10-IDEX-0001-02 PSL*, ANR-11-LABX-0043]
- ANR INNATENUCLEOTIDES
- Fondation BMS
- ACTERIA Foundation
- Fondation Schlumberger pour l'Education et la Recherche (FSER)
- ANRS (France Recherche Nord & Sud Sida-hiv Hepatites) [ECTZ25472, ECTZ36691]
- Sidaction [VIH2016126002]
- DIM Biotherapies
- European Research Council [309848 HIVINNATE, 727408 STIMUNITY]
- French Ministry of Education, Research, and Technology
- Marie Sklodowska-Curie Individual Fellowship [DCBIO 751735]
- EMBO Long-term fellowship [ALTF 1298-2016]
Cytosolic DNA activates cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS), an innate immune sensor pivotal in antimicrobial 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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