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

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.
Mesh Terms:
A549 Cells, Angiopoietin-like Proteins, Animals, Autophagy, Gene Expression Regulation, HEK293 Cells, Hep G2 Cells, Humans, I-kappa B Kinase, Inflammation, Interleukin-1beta, Male, Mice, Inbred C57BL, NF-kappa B, Peptide Hormones, Sequestosome-1 Protein
Nat Commun
Date: Dec. 18, 2016
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