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PMID:30135424

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Citation

Lian, H, Wei, J, Zang, R, Ye, W, Yang, Q, Zhang, XN, Chen, YD, Fu, YZ, Hu, MM, Lei, CQ, Luo, WW, Li, S and Shu, HB (2018) ZCCHC3 is a co-sensor of cGAS for dsDNA recognition in innate immune response. Nat Commun 9:3349

Abstract

Cyclic GMP-AMP synthase (cGAS) senses double-strand (ds) DNA in the cytosol and then catalyzes synthesis of the second messenger cGAMP, which activates the adaptor MITA/STING to initiate innate antiviral response. How cGAS activity is regulated remains enigmatic. Here, we identify ZCCHC3, a CCHC-type zinc-finger protein, as a positive regulator of cytosolic dsDNA- and DNA virus-triggered signaling. We show that ZCCHC3-deficiency inhibits dsDNA- and DNA virus-triggered induction of downstream effector genes, and that ZCCHC3-deficient mice are more susceptible to lethal herpes simplex virus type 1 or vaccinia virus infection. ZCCHC3 directly binds to dsDNA, enhances the binding of cGAS to dsDNA, and is important for cGAS activation following viral infection. Our results suggest that ZCCHC3 is a co-sensor for recognition of dsDNA by cGAS, which is important for efficient innate immune response to cytosolic dsDNA and DNA virus.

Links

PubMed PMC6105683 Online version:10.1038/s41467-018-05559-w

Keywords

Animals; DNA/genetics; DNA/metabolism; Immunity, Innate/genetics; Immunity, Innate/physiology; Mice; Mice, Knockout; Nucleotides, Cyclic/metabolism; Nucleotidyltransferases/genetics; Nucleotidyltransferases/metabolism; RNA Nucleotidyltransferases/genetics; RNA Nucleotidyltransferases/metabolism; Signal Transduction/genetics; Signal Transduction/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:ZCHC3

involved_in

GO:0002218: activation of innate immune response

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ZCHC3

involved_in

GO:0032481: positive regulation of type I interferon production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ZCHC3

involved_in

GO:0051607: defense response to virus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ZCHC3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8N884

F

Seeded From UniProt

complete

HUMAN:ZCHC3

involved_in

GO:0002218: activation of innate immune response

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ZCHC3

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:ZCHC3

involved_in

GO:0009597: detection of virus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ZCHC3

enables

GO:0003690: double-stranded DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:CGAS

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9NUD5

F

Seeded From UniProt


Notes

See also

References

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