NLRC3 is a negative regulator of DNA-induced immune response Public Deposited

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Last Modified
  • June 7, 2019
Creator
  • Zhang, Lu
    • Affiliation: School of Dentistry, Oral and Craniofacial Biomedicine PhD Program
Abstract
  • Innate immunity provides the first line of defense and the pattern recognition receptors (PRRs) are indispensible in sensing foreign insults and self-damage. Recent research interests have been focused on elucidating cytosolic DNA recognition and downstream signaling activation. Stimulator of interferon genes (STING, also named MITA, MYPS or ERIS) is an intracellular DNA sensor that activates type I interferon production through its interaction with TANK-binding kinase 1 (TBK1). STING recognizes cytosolic dsDNA, DNA viruses, cyclic di-GMP (c-di-GMP), c-di-GMP-producing bacteria as well as other intracellular DNA sensors. Here we found that the nucleotide-binding, leucine-rich repeat containing protein, NLRC3, inhibited STING-dependent innate immune activation in response to cytosolic dsDNA, c-di-GMP and DNA viruses. Mechanistically, NLRC3 associated with both STING and TBK1, and impeded STING-TBK1 interaction and downstream type I interferon production. Using purified recombinant proteins NLRC3 was found to interact directly with STING. Furthermore, NLRC3 blocked proper trafficking of STING to perinuclear and punctated region, which is known to be essential for its activation. In animals, herpes simplex virus 1 (HSV-1)-infected Nlrc3-/- mice exhibited enhanced innate immunity, 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. In addition, NLRC3 directly bound to DNA, specifically to double-stranded and single-stranded junction of DNA and DNA replication fork with 25 base pair single-stranded region shown by incubation of purified recombinant NLRC3 and DNA in a cell-free system. In an ultraviolet (UV) light-induced DNA damage model, Nlrc3-/- cells displayed elevated activation of innate immune activation, potentially triggered by damaged DNA. These findings collectively suggest a novel role of NLRC3 in STING-dependent pathways, DNA-damage-induced innate immune activation and pathways beyond immune regulation.
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  • In Copyright
Advisor
  • Ting, Jenny P.-Y.
Degree
  • Doctor of Philosophy
Graduation year
  • 2014
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