Tongji School of Pharmacy, Huazhong University of Science & Technology, Wuhan, 430030, China.
Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, China.
Nat Commun. 2017 Dec 18;8(1):2164. doi: 10.1038/s41467-017-02355-w.
Excessive nuclear factor-κB (NF-κB) activation mediated by tumor necrosis factor α (TNFα) plays a critical role in inflammation. Here we demonstrate that angiopoietin-like 8 (ANGPTL8) functions as a negative feedback regulator in TNFα-triggered NF-κB activation intracellularly. Inflammatory stimuli induce ANGPTL8 expression, and knockdown or knockout of ANGPTL8 potentiates TNFα-induced NF-κB activation in vitro. Mechanistically, upon TNFα stimulation, ANGPTL8 facilitates the interaction of IKKγ with p62 via forming a complex, thus promoting the selective autophagic degradation of IKKγ. Furthermore, the N-terminal domain mediated self-oligomerization of ANGPTL8 is essential for IKKγ degradation and NF-κB activation. In vivo, circulating ANGPTL8 level is high in patients diagnosed with infectious diseases, and the ANGPTL8/p62-IKKγ axis is responsive to inflammatory stimuli in the liver of LPS-injected mice. Altogether, our study suggests the ANGPTL8/p62-IKKγ axis as a negative feedback loop that regulates NF-κB activation, and extends the role of selective autophagy in fine-tuned inflammatory responses.
过度的核因子-κB（NF-κB）激活是由肿瘤坏死因子α（TNFα）介导的，在炎症中起着关键作用。在这里，我们证明了血管生成素样蛋白 8（ANGPTL8）作为 TNFα触发的 NF-κB 激活的负反馈调节剂在细胞内起作用。炎症刺激诱导 ANGPTL8 的表达，而 ANGPTL8 的敲低或敲除增强了 TNFα诱导的 NF-κB 体外激活。在机制上，在 TNFα刺激下，ANGPTL8 通过形成复合物促进 IKKγ 与 p62 的相互作用，从而促进 IKKγ 的选择性自噬降解。此外，ANGPTL8 的 N 端结构域介导的自寡聚化对于 IKKγ 的降解和 NF-κB 的激活是必需的。在体内，患有传染病的患者的循环 ANGPTL8 水平较高，并且 LPS 注射小鼠肝脏中的 ANGPTL8/p62-IKKγ 轴对炎症刺激有反应。总之，我们的研究表明，ANGPTL8/p62-IKKγ 轴作为一种负反馈回路，调节 NF-κB 的激活，并扩展了选择性自噬在精细炎症反应中的作用。
