title: The innate immune sensor NLRC3 attenuates Toll-like receptor signaling via modification of the signaling adaptor TRAF6 and transcription factor NF-κB.
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.
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Monika
authors.initials: M
authors.lastname: Schneider
authors.forename: Albert G
authors.initials: AG
authors.lastname: Zimmermann
authors.forename: Reid A
authors.initials: RA
authors.lastname: Roberts
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.forename: Karen V
authors.initials: KV
authors.lastname: Swanson
authors.forename: Haitao
authors.initials: H
authors.lastname: Wen
authors.forename: Beckley K
authors.initials: BK
authors.lastname: Davis
authors.forename: Irving C
authors.initials: IC
authors.lastname: Allen
authors.forename: Eda K
authors.initials: EK
authors.lastname: Holl
authors.forename: Zhengmao
authors.initials: Z
authors.lastname: Ye
authors.forename: Adeeb H
authors.initials: AH
authors.lastname: Rahman
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Conti
authors.forename: Timothy K
authors.initials: TK
authors.lastname: Eitas
authors.forename: Beverly H
authors.initials: BH
authors.lastname: Koller
authors.forename: Jenny P-Y
authors.initials: JP
authors.lastname: Ting
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D025461:Feedback, Physiological; D057809:HEK293 Cells; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000276:immunology* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D048029:TNF Receptor-Associated Factor 6 / Q000276:immunology* / Q000378:metabolism; D051193:Toll-Like Receptors / Q000276:immunology* / Q000378:metabolism; D054380:Receptors, CXCR5
chemical_list: D016328:NF-kappa B; D043562:Receptors, G-Protein-Coupled; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors; C513179:CXCR5 protein, mouse; D054380:Receptors, CXCR5