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The innate immune sensor NLRC3 attenuates Toll-like receptor signaling via modification of the signaling adaptor TRAF6 and transcription factor NF-κB.

Several members of the NLR family of sensors activate innate immunity. In contrast, we found here that NLRC3 inhibited Toll-like receptor (TLR)-dependent activation of the transcription factor NF-κB by interacting with the TLR signaling adaptor TRAF6 to attenuate Lys63 (K63)-linked ubiquitination of TRAF6 and activation of NF-κB. We used bioinformatics to predict interactions between NLR and TRAF proteins, including interactions of TRAF with NLRC3. In vivo, macrophage expression of Nlrc3 mRNA was diminished by the administration of lipopolysaccharide (LPS) but was restored when cellular activation subsided. To assess biologic relevance, we generated Nlrc3(-/-) mice. LPS-treated Nlrc3(-/-) macrophages had more K63-ubiquitinated TRAF6, nuclear NF-κB and proinflammatory cytokines. Finally, LPS-treated Nlrc3(-/-) mice had more signs of inflammation. Thus, signaling via NLRC3 and TLR constitutes a negative feedback loop. Furthermore, prevalent NLR-TRAF interactions suggest the formation of a 'TRAFasome' complex.

Pubmed ID: 22863753


  • Schneider M
  • Zimmermann AG
  • Roberts RA
  • Zhang L
  • Swanson KV
  • Wen H
  • Davis BK
  • Allen IC
  • Holl EK
  • Ye Z
  • Rahman AH
  • Conti BJ
  • Eitas TK
  • Koller BH
  • Ting JP


Nature immunology

Publication Data

September 23, 2012

Associated Grants

  • Agency: NIDDK NIH HHS, Id: K01 DK092355
  • Agency: NIAID NIH HHS, Id: R37 AI029564
  • Agency: NIAID NIH HHS, Id: R37-AI029564
  • Agency: NIAMS NIH HHS, Id: T32-AR007416
  • Agency: NIAID NIH HHS, Id: U19 AI077437
  • Agency: NIAID NIH HHS, Id: U19-AI1077437
  • Agency: NIAID NIH HHS, Id: U54 AI057157
  • Agency: NIAID NIH HHS, Id: U54-AI057157

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Feedback, Physiological
  • HEK293 Cells
  • Humans
  • Macrophages
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Sequence Data
  • NF-kappa B
  • Real-Time Polymerase Chain Reaction
  • Receptors, G-Protein-Coupled
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • TNF Receptor-Associated Factor 6
  • Toll-Like Receptors