ANGPTL8 negatively regulates NF-κB activation by facilitating selective autophagic degradation of IKKγ

作者：Yu Zhang, Xian Guo, Wanyao Yan, Yan Chen, Mengxiang Ke, Cheng Cheng, Xiuqin Zhu, Weili Xue, Qiaoqiao Zhou, Ling Zheng, Shun Wang, Bin Wu, Xinran Liu, Liang Ma, Lianqi Huang, Kun Huang · 发表于：Nature Communications · 年份：2017 · DOI：10.1038/s41467-017-02355-w · 被引用次数：110 · 研究领域：Lipid metabolism and disorders、Cancer-related molecular mechanisms research、Autophagy in Disease and Therapy

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.