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

Monika Schneider, Albert G. Zimmermann, Reid A. Roberts, Lu Zhang, Karen V. Swanson, Haitao Wen, Beckley K. Davis, Irving C. Allen, Eda K. Holl, Zhengmao Ye, Adeeb H. Rahman, Brian J. Conti, Timothy K. Eitas, Beverly H. Koller, Jenny P.Y. Ting

Research output: Contribution to journalArticle

155 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)823-831
Number of pages9
JournalNature Immunology
Volume13
Issue number9
DOIs
StatePublished - Sep 1 2012

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TNF Receptor-Associated Factor 6
Toll-Like Receptors
Lipopolysaccharides
Transcription Factors
Macrophages
Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
Ubiquitination
Computational Biology
Innate Immunity
Cytokines
Inflammation
Messenger RNA

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Schneider, M., Zimmermann, A. G., Roberts, R. A., Zhang, L., Swanson, K. V., Wen, H., ... Ting, J. P. Y. (2012). The innate immune sensor NLRC3 attenuates Toll-like receptor signaling via modification of the signaling adaptor TRAF6 and transcription factor NF-κB. Nature Immunology, 13(9), 823-831. https://doi.org/10.1038/ni.2378

The innate immune sensor NLRC3 attenuates Toll-like receptor signaling via modification of the signaling adaptor TRAF6 and transcription factor NF-κB. / Schneider, Monika; Zimmermann, Albert G.; Roberts, Reid A.; Zhang, Lu; Swanson, Karen V.; Wen, Haitao; Davis, Beckley K.; Allen, Irving C.; Holl, Eda K.; Ye, Zhengmao; Rahman, Adeeb H.; Conti, Brian J.; Eitas, Timothy K.; Koller, Beverly H.; Ting, Jenny P.Y.

In: Nature Immunology, Vol. 13, No. 9, 01.09.2012, p. 823-831.

Research output: Contribution to journalArticle

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, JPY 2012, 'The innate immune sensor NLRC3 attenuates Toll-like receptor signaling via modification of the signaling adaptor TRAF6 and transcription factor NF-κB', Nature Immunology, vol. 13, no. 9, pp. 823-831. https://doi.org/10.1038/ni.2378
Schneider, Monika ; Zimmermann, Albert G. ; Roberts, Reid A. ; Zhang, Lu ; Swanson, Karen V. ; Wen, Haitao ; Davis, Beckley K. ; Allen, Irving C. ; Holl, Eda K. ; Ye, Zhengmao ; Rahman, Adeeb H. ; Conti, Brian J. ; Eitas, Timothy K. ; Koller, Beverly H. ; Ting, Jenny P.Y. / The innate immune sensor NLRC3 attenuates Toll-like receptor signaling via modification of the signaling adaptor TRAF6 and transcription factor NF-κB. In: Nature Immunology. 2012 ; Vol. 13, No. 9. pp. 823-831.
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