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.
Highlights
Excessive nuclear factor-κB (NF-κB) activation mediated by tumor necrosis factor α (TNFα) plays a critical role in inflammation
angiopoietin-like 8 (ANGPTL8) regulates lipid metabolism, and the level of circulating ANGPTL8 is increased in type 2 diabetes (T2D)[21,22]
Since lipid toxicity and T2D are tightly correlated with inflammation, we investigated the level of ANGPTL8 upon stimulation of pro-inflammatory cytokines such as TNFα and IL-1β
Summary
Excessive nuclear factor-κB (NF-κB) activation mediated by tumor necrosis factor α (TNFα) plays a critical role in inflammation. 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. Many agents, including pro-inflammatory cytokines, cause phosphorylation and degradation of IκBα, which results in releasing of NF-κB for translocation to the nucleus and initiating the expression of downstream genes[2]. Among these agentsmediated signaling, TNFα induction is a classical model to study the regulatory mechanisms of NF-κB activation. We demonstrate intracellular ANGPTL8 as a novel negative feedback regulator of TNFα-mediated NF-κB activation, which may work as a critical step to avoid excessive inflammatory responses by facilitating p62-mediated autophagic IKKγ degradation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
