Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Nat Immunol. 2012 Sep;13(9):823-31. doi: 10.1038/ni.2378. Epub 2012 Aug 5.
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.
几种 NLR 家族传感器成员激活先天免疫。相比之下，我们在这里发现 NLRC3 通过与 TLR 信号适配器 TRAF6 相互作用来抑制 TLR 依赖性转录因子 NF-κB 的激活，从而减弱 TRAF6 的 Lys63 (K63)-连接泛素化和 NF-κB 的激活。我们使用生物信息学预测 NLR 和 TRAF 蛋白之间的相互作用，包括 TRAF 与 NLRC3 的相互作用。在体内，巨噬细胞中 Nlrc3 mRNA 的表达被脂多糖 (LPS) 处理减弱，但当细胞激活减弱时恢复。为了评估生物学相关性，我们生成了 Nlrc3(-/-) 小鼠。用 LPS 处理的 Nlrc3(-/-) 巨噬细胞中具有更多的 K63 连接的 TRAF6、核 NF-κB 和促炎细胞因子。最后，用 LPS 处理的 Nlrc3(-/-) 小鼠有更多的炎症迹象。因此，NLRC3 和 TLR 的信号转导构成了一个负反馈回路。此外，普遍存在的 NLR-TRAF 相互作用表明形成了一个“TRAFasome”复合物。
