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

159 Scopus citations

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
Publication statusPublished - Sep 1 2012

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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