ANGPTL3 negatively regulates IL-1ß-induced NF-κB activation by inhibiting the IL1R1-associated signaling complex assembly.

Interleukin-1ß (IL-1ß)-induced signaling is one of the most important pathways in regulating inflammation and immunity. The assembly of the receptor complex, consisting of the ligand IL-1ß, the IL-1 receptor (IL-1R) type 1 (IL1R1), and the IL-1R accessory protein (IL1RAP), initiates this signaling. However, how the IL1R1-associated complex is regulated remains elusive. Angiopoietin like 3 (ANGPTL3), a key inhibitor of plasma triglyceride clearance, is mainly expressed in the liver and exists in both intracellular and extracellular secreted forms. Presently, ANGPTL3 has emerged as a highly promising drug target for hypertriglyceridemia and associated cardiovascular diseases. However, most studies have focused on the secreted form of ANGPTL3, while its intracellular role is still largely unknown. Here, we report that intracellular ANGPTL3 acts as a negative regulator of IL-1ß-triggered signaling. Overexpression of ANGPTL3 inhibited IL-1ß-induced NF-κB activation and the transcription of inflammatory genes in HepG2, THP1, and HEK293T cells, while knockdown or knockout of ANGPTL3 resulted in opposite effects. Mechanistically, ANGPTL3 interacted with IL1R1 and IL1RAP through its intracellular C-terminal fibrinogen-like domain (FLD) and disrupted the assembly of the IL1R1-associated complex. Taken together, our study reveals a novel role for ANGPTL3 in inflammation, whereby it inhibits the physiological interaction between IL1R1 and IL1RAP to maintain immune tolerance and homeostasis in the liver.

A rapid analytical method for the quantitative determination of the sugar in acarbose fermentation by infrared spectroscopy and chemometrics.

In this article, a rapid analytical method for the quantitative determination of the glucose and maltose in the industrial acarbose fermentation was established by the combination application of infrared spectroscopy and chemometrics. The spectra of the 398 acarbose samples were collected by a portable infrared fast analyzer and the concentration of the glucose and maltose in the acarbose fermentation solution were determinate by high performance liquid chromatography (HPLC) as the referent database. Four spectral pretreatment methods, first derivative (FD), second derivative (SD), Savitzky-Golay (SG) convolution smoothing and mean center (MC) were employed to eliminate the optical interference from background and other noise information. The best result was obtained with FD+SG(21, 3)+MC method. The effects of different principal component numbers (PCs) on the parameters were also optimized. Two models of PLS and MLR, were used to predict the concentration of the glucose and maltose. The FD+SG(21, 3)+MC method was chosen as best method, with 12 PCs for glucose and 11 for maltose as optimized parameters. The PLS model was significantly better than the MLR model. Furthermore, both the predicted values and the reference values of glucose and maltose models showed superior linear relationship within the calibration range. The absolute errors of the predicted values and their corresponding reference values of glucose and maltose in the PLS model were within ±0.14 and ±0.35 confidence intervals, respectively. The prediction correct rate was 98.3%, which indicated that the prediction results of model were excellent.

USP15 potentiates NF-κB activation by differentially stabilizing TAB2 and TAB3.

Tumor necrosis factor α (TNFα)- and interleukin 1ß (IL-1ß)-induced nuclear factor-κB (NF-κB) activation play key roles in inflammation, immunity, and cancer development. Here, we identified one of the deubiquitinating enzymes (DUBs), ubiquitin-specific protease 15 (USP15), as a positive regulator in both TNFα- and IL-1ß-induced NF-κB activation. Overexpression of USP15 potentiated TNFα- or IL-1ß-triggered NF-κB activation and downstream gene transcription, whereas knockdown of USP15 had opposite effects. Mechanistically, upon TNFα stimulation, USP15 showed an enhanced interaction with transforming growth factor-ß activated kinase-1 (TAK1)-TAK1 binding protein (TAB) complex to inhibit the proteolysis of TAB2/3 by different pathways. Apart from deubiquitination dependently inducing cleavage of lysine 48-linked TAB2 ubiquitination, USP15 also DUB independently inhibited lysosome-associated TAB2 degradation, thus enhanced TAB2 stabilization. For TAB3, USP15 inhibited NBR1-mediated selective autophagic TAB3 degradation independent of its deubiquitinating activity. Together, our results reveal a novel USP15-mediated mechanism through which efficient NF-κB activation is achieved by differentially maintaining the TAB2/3 stability.