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

 Schneider, M. et al. Nat. Immunol. 11, 823-831, 2012

Speaker: Chung-Tend Wang (王崇騰)                  Time: 14:00~15:00, Dec. 12, 2012

Commentator: Dr. Pin Ling (凌斌老師)              Place: Room 601

Abstract

The NLR (nucleotide-binding, leucine-rich repeat-containing) family of sensors has many functions, including inflammatory and anti-inflammatory roles.¹ Activation of NF-κB is a key regulator of inflammation and can be promoted through various stimuli, which results in the production ofproinflammatory cytokines. Both nucleotide-binding oligomerization domain protein 1 (Nod1) and Nod2 associate with the adap­tor RIP2 (receptor interacting protein 2), which can lead to its Lys63-linked ubiquitination and enhancement of the activa­tion of NF-κB.² NF-κB activation is diminished in the presence of overexpressed NLRC3 in cell lines.³ In this study, the authors showed 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-linkedubiquitination of TRAF6 and activation of NF-κB. They 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, they 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.

References

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2          Bertrand, M. J. et al. Cellular inhibitors of apoptosis cIAP1 and cIAP2 are required for innate immunity signaling by the pattern recognition receptors NOD1 and NOD2. Immunity 30, 789-801, 2009.

3          Conti, B. J. et al. CATERPILLER 16.2 (CLR16.2), a novel NBD/LRR family member that negatively regulates T cell function. J. Biol. Chem. 280, 18375-18385, 2005.