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

Immunity. 2014 Mar 20;40(3):329-41. doi: 10.1016/j.immuni.2014.01.010. Epub 2014 Feb 20.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*

Substances

  • Cytokines
  • Intercellular Signaling Peptides and Proteins
  • Interferon Type I
  • Membrane Proteins
  • NLRC3 protein, mouse
  • Sting1 protein, mouse
  • bis(3',5')-cyclic diguanylic acid
  • DNA
  • Tbk1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Cyclic GMP