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

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.

Hepatocellular Carcinoma‐Associated Protein TD26 Interacts and Enhances Sterol Regulatory Element‐Binding Protein 1 Activity to Promote Tumor Cell Proliferation and Growth

“…For example, Zhang et al have recently demonstrated that TD26 can negatively regulate nuclear factor kappa B intracellularly, and TD26 self‐oligomerization is essential for this negative regulation. Interestingly, the N‐terminal signal peptide (secretory signal peptide) of TD26 is not required for such self‐oligomerization . To further characterize the subcellular localization of TD26 in HCC in vivo , we examined our TD26 IHC results in HCC samples.…”

“…TD26 is a well-known secretory protein produced by liver and adipose tissues, but some recent studies have also demonstrated an intracellular function of TD26. (38) For example, Zhang et al have recently demonstrated that TD26 can negatively regulate nuclear factor kappa B intracellularly, and TD26 self-oligomerization is essential for this negative regulation. Interestingly, the N-terminal signal peptide (secretory signal peptide) of TD26 is not required for such self-oligomerization.…”

Histone demethylase UTX is a therapeutic target for diabetic kidney disease

“…; Zhang et al . ). Some 20–80 μg of proteins from each sample were separated by SDS‐PAGE and transferred onto polyvinylidene difluoride (PVDF) membranes for immunodetection.…”

Lmo4‐resistin signaling contributes to adipose tissue‐liver crosstalk upon weight cycling

“…Freshly isolated cultured cells or tissues were sonicated in ice‐cold RIPA buffer (Beyotime) and protein concentrations were determined using BCA Protein Assay Kit (Cowin). Proteins were fractionated by SDS‐PAGE, electroblotted onto PVDF membrane (Millipore) and probed with primary antibodies including Lmo4 (81428, Cell Signaling, Danvers, MA), Resistin (NBP1‐45839, Novus Biologicals, Oakville, Canada), Hsp70 (610607, BD Pharmingen, San Jose, CA), β‐actin (133626, Abcam, Cambridge, MA), PEPCK (32879, Santa Cruz), G6PC (27198, Santa Cruz), PFK (97444, Abcam), PK (133222, Santa Cruz), STAT3 (51076, Proteintech, Wuhan, China), p‐STAT3 Tyr705 (9131, Cell Signaling), visualized by enhanced chemiluminescence (Pierce, Rockford, IL), and evaluated using Quantity One Software (Bio‐Rad) . Densities of target proteins and loading controls were quantitated, the relative protein expression level in different groups was reported as the density of target protein vs that of loading control.…”