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PMID:24560620

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Citation

Zhang, L, Mo, J, Swanson, KV, Wen, H, Petrucelli, A, Gregory, SM, Zhang, Z, Schneider, M, Jiang, Y, Fitzgerald, KA, Ouyang, S, Liu, ZJ, Damania, B, Shu, HB, Duncan, JA and Ting, JP (2014) NLRC3, a member of the NLR family of proteins, is a negative regulator of innate immune signaling induced by the DNA sensor STING. Immunity 40:329-41

Abstract

Stimulator of interferon genes (STING, also named MITA, MYPS, or ERIS) is an intracellular DNA sensor that induces type I interferon through its interaction with TANK-binding kinase 1 (TBK1). Here we found that the nucleotide-binding, leucine-rich-repeat-containing protein, NLRC3, reduced STING-dependent innate immune activation in response to cytosolic DNA, cyclic di-GMP (c-di-GMP), and DNA viruses. NLRC3 associated with both STING and TBK1 and impeded STING-TBK1 interaction and downstream type I interferon production. By using purified recombinant proteins, we found NLRC3 to interact directly with STING. Furthermore, NLRC3 prevented proper trafficking of STING to perinuclear and punctated region, known to be important for its activation. In animals, herpes simplex virus 1 (HSV-1)-infected Nlrc3(-/-) mice exhibited enhanced innate immunity and reduced morbidity and viral load. This demonstrates the intersection of two key pathways of innate immune regulation, NLR and STING, to fine tune host response to intracellular DNA, DNA virus, and c-di-GMP.

Links

PubMed PMC4011014 Online version:10.1016/j.immuni.2014.01.010

Keywords

Animals; Cell Line; Cyclic GMP/analogs & derivatives; Cyclic GMP/pharmacology; Cytokines/biosynthesis; DNA/immunology; Herpes Simplex/immunology; Herpes Simplex/metabolism; Herpesvirus 1, Human/physiology; Humans; Immunity, Innate; Intercellular Signaling Peptides and Proteins/deficiency; Intercellular Signaling Peptides and Proteins/genetics; Intercellular Signaling Peptides and Proteins/metabolism; Interferon Type I/biosynthesis; Membrane Proteins/metabolism; Mice; Mice, Knockout; Protein Binding; Protein Transport; Protein-Serine-Threonine Kinases/metabolism; Signal Transduction

Significance

Annotations

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

MOUSE:STING

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:STING

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9WUN2

F

Seeded From UniProt

complete

HUMAN:NLRC3

located_in

GO:0048471: perinuclear region of cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:NLRC3

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:NLRC3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q86WV6

F

Seeded From UniProt

complete

HUMAN:NLRC3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9UHD2

F

Seeded From UniProt

complete

HUMAN:STING

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q7RTR2

F

Seeded From UniProt

complete

HUMAN:TBK1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q7RTR2

F

Seeded From UniProt

complete

MOUSE:TBK1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q3TBT3

F

Seeded From UniProt

complete

HUMAN:NLRC3

part_of

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:NLRC3

part_of

GO:0048471: perinuclear region of cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:NLRC3

involved_in

GO:0032715: negative regulation of interleukin-6 production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NLRC3

involved_in

GO:0032688: negative regulation of interferon-beta production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NLRC3

involved_in

GO:0032687: negative regulation of interferon-alpha production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NLRC3

involved_in

GO:1900016: negative regulation of cytokine production involved in inflammatory response

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NLRC3

involved_in

GO:0045824: negative regulation of innate immune response

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NLRC3

involved_in

GO:0050728: negative regulation of inflammatory response

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:STING

part_of

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

Notes

See also

References

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