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

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 and Kun Huang ()
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Yu Zhang: Huazhong University of Science & Technology
Xian Guo: Huazhong University of Science & Technology
Wanyao Yan: Huazhong University of Science & Technology
Yan Chen: Huazhong University of Science & Technology
Mengxiang Ke: Huazhong University of Science & Technology
Cheng Cheng: Huazhong University of Science & Technology
Xiuqin Zhu: Wuhan University
Weili Xue: Wuhan University
Qiaoqiao Zhou: Huazhong University of Science & Technology
Ling Zheng: Wuhan University
Shun Wang: Wuhan Hospital of Traditional and Western Medicine
Bin Wu: Wuhan Hospital of Traditional and Western Medicine
Xinran Liu: Huazhong University of Science & Technology
Liang Ma: Huazhong University of Science & Technology
Lianqi Huang: Huazhong University of Science & Technology
Kun Huang: Huazhong University of Science & Technology

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-02355-w

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