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

• Published in: Nature immunology Vol. 13; no. 9; pp. 823 - 831
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2012; Nature Publishing Group
• Subjects: 631/1647/48; 631/250/2502; 631/250/256; 631/250/516; Amino Acid Sequence; Animals; Biomedical and Life Sciences; Biomedicine; Cytokines; Feedback, Physiological; HEK293 Cells; Humans; Immunology; Infectious Diseases; Macrophages - immunology; Macrophages - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Sequence Data; NF-kappa B - immunology; NF-kappa B - metabolism; Physiological aspects; Real-Time Polymerase Chain Reaction; Receptors, G-Protein-Coupled - immunology; Receptors, G-Protein-Coupled - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction - immunology; TNF Receptor-Associated Factor 6 - immunology; TNF Receptor-Associated Factor 6 - metabolism; Toll-like receptors; Toll-Like Receptors - immunology; Toll-Like Receptors - metabolism; Transcription factors; United States
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni.2378

Sensors of the NLR family generally activate innate immunity. Ting et al ., however, demonstrate that the little-known NLRC3 negatively regulates Toll-like receptor signaling by altering ubiquitination of the signaling adaptor TRAF6. 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.