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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.

Publication ,  Journal Article
Schneider, M; Zimmermann, AG; Roberts, RA; Zhang, L; Swanson, KV; Wen, H; Davis, BK; Allen, IC; Holl, EK; Ye, Z; Rahman, AH; Conti, BJ ...
Published in: Nat Immunol
September 2012

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.

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Published In

Nat Immunol

DOI

EISSN

1529-2916

Publication Date

September 2012

Volume

13

Issue

9

Start / End Page

823 / 831

Location

United States

Related Subject Headings

  • Toll-Like Receptors
  • TNF Receptor-Associated Factor 6
  • Signal Transduction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Receptors, G-Protein-Coupled
  • Real-Time Polymerase Chain Reaction
  • NF-kappa B
  • Molecular Sequence Data
  • Mice, Knockout
  • Mice, Inbred C57BL
 

Citation

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Chicago
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MLA
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Schneider, M., Zimmermann, A. G., Roberts, R. A., Zhang, L., Swanson, K. V., Wen, H., … Ting, J.-Y. (2012). The innate immune sensor NLRC3 attenuates Toll-like receptor signaling via modification of the signaling adaptor TRAF6 and transcription factor NF-κB. Nat Immunol, 13(9), 823–831. https://doi.org/10.1038/ni.2378
Schneider, Monika, Albert G. Zimmermann, Reid A. Roberts, Lu Zhang, Karen V. Swanson, Haitao Wen, Beckley K. Davis, et al. “The innate immune sensor NLRC3 attenuates Toll-like receptor signaling via modification of the signaling adaptor TRAF6 and transcription factor NF-κB.Nat Immunol 13, no. 9 (September 2012): 823–31. https://doi.org/10.1038/ni.2378.
Schneider M, Zimmermann AG, Roberts RA, Zhang L, Swanson KV, Wen H, et al. The innate immune sensor NLRC3 attenuates Toll-like receptor signaling via modification of the signaling adaptor TRAF6 and transcription factor NF-κB. Nat Immunol. 2012 Sep;13(9):823–31.
Schneider, Monika, et al. “The innate immune sensor NLRC3 attenuates Toll-like receptor signaling via modification of the signaling adaptor TRAF6 and transcription factor NF-κB.Nat Immunol, vol. 13, no. 9, Sept. 2012, pp. 823–31. Pubmed, doi:10.1038/ni.2378.
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-Y. The innate immune sensor NLRC3 attenuates Toll-like receptor signaling via modification of the signaling adaptor TRAF6 and transcription factor NF-κB. Nat Immunol. 2012 Sep;13(9):823–831.

Published In

Nat Immunol

DOI

EISSN

1529-2916

Publication Date

September 2012

Volume

13

Issue

9

Start / End Page

823 / 831

Location

United States

Related Subject Headings

  • Toll-Like Receptors
  • TNF Receptor-Associated Factor 6
  • Signal Transduction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Receptors, G-Protein-Coupled
  • Real-Time Polymerase Chain Reaction
  • NF-kappa B
  • Molecular Sequence Data
  • Mice, Knockout
  • Mice, Inbred C57BL