ANGPTL8 negatively regulates NF-?B activation by facilitating selective autophagic degradation of IKK?.

ABSTRACT: Excessive nuclear factor-?B (NF-?B) activation mediated by tumor necrosis factor ? (TNF?) plays a critical role in inflammation. Here we demonstrate that angiopoietin-like 8 (ANGPTL8) functions as a negative feedback regulator in TNF?-triggered NF-?B activation intracellularly. Inflammatory stimuli induce ANGPTL8 expression, and knockdown or knockout of ANGPTL8 potentiates TNF?-induced NF-?B activation in vitro. Mechanistically, upon TNF? stimulation, ANGPTL8 facilitates the interaction of IKK? with p62 via forming a complex, thus promoting the selective autophagic degradation of IKK?. Furthermore, the N-terminal domain mediated self-oligomerization of ANGPTL8 is essential for IKK? degradation and NF-?B activation. In vivo, circulating ANGPTL8 level is high in patients diagnosed with infectious diseases, and the ANGPTL8/p62-IKK? axis is responsive to inflammatory stimuli in the liver of LPS-injected mice. Altogether, our study suggests the ANGPTL8/p62-IKK? axis as a negative feedback loop that regulates NF-?B activation, and extends the role of selective autophagy in fine-tuned inflammatory responses.

SUBMITTER: Zhang Y 

PROVIDER: S-EPMC5735157 | biostudies-other | 2017 Dec

REPOSITORIES: biostudies-other