NLRC3, a member of the NLR family of proteins, is a negative regulator of innate immune signaling induced by the DNA sensor STING

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-depe...

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Published in:Immunity (Cambridge, Mass.) Vol. 40; no. 3; p. 329
Main Authors: Zhang, Lu, Mo, Jinyao, Swanson, Karen V, Wen, Haitao, Petrucelli, Alex, Gregory, Sean M, Zhang, Zhigang, Schneider, Monika, Jiang, Yan, Fitzgerald, Katherine A, Ouyang, Songying, Liu, Zhi-Jie, Damania, Blossom, Shu, Hong-Bing, Duncan, Joseph A, Ting, Jenny P-Y
Format: Journal Article
Language:English
Published: United States 20.03.2014
Subjects:
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
ISSN:1097-4180, 1097-4180
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Summary: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.
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ISSN:1097-4180
1097-4180
DOI:10.1016/j.immuni.2014.01.010