title: NLRC3, a member of the NLR family of proteins, is a negative regulator of innate immune signaling induced by the DNA sensor STING.
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.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Oral Biology, School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Division of Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Jinyao
authors.initials: J
authors.lastname: Mo
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Karen V
authors.initials: KV
authors.lastname: Swanson
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Haitao
authors.initials: H
authors.lastname: Wen
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Petrucelli
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Gregory
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Monika
authors.initials: M
authors.lastname: Schneider
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Songying
authors.initials: S
authors.lastname: Ouyang
authors.affiliation: iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
authors.forename: Zhi-Jie
authors.initials: ZJ
authors.lastname: Liu
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Blossom
authors.initials: B
authors.lastname: Damania
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Hong-Bing
authors.initials: HB
authors.lastname: Shu
authors.affiliation: Department of Medicine, Division of Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Duncan
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Institute of Inflammatory Diseases and Center for Translational Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: jenny_ting@med.unc.edu.
authors.forename: Jenny P-Y
authors.initials: JP
authors.lastname: Ting
mesh_terms: D000818:Animals; D002460:Cell Line; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D004247:DNA / Q000276:immunology*; D006561:Herpes Simplex / Q000276:immunology / Q000378:metabolism; D018259:Herpesvirus 1, Human / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D007370:Interferon Type I / Q000096:biosynthesis; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport; D015398:Signal Transduction; D000099197:STING Protein
chemical_list: D006152:Cyclic GMP; D016207:Cytokines; D004247:DNA; D036341:Intercellular Signaling Peptides and Proteins; D007370:Interferon Type I; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; C588347:NLRC3 protein, mouse; C530855:Sting1 protein, mouse; D000099197:STING Protein; C062025:bis(3',5')-cyclic diguanylic acid; C498588:Tbk1 protein, mouse