Natural small molecule FMHM inhibits lipopolysaccharide-induced inflammatory response by promoting TRAF6 degradation via K48-linked polyubiquitination

Abstract

TNF receptor-associated factor 6 (TRAF6) is a key hub protein involved in Toll-like receptor-dependent inflammatory signaling pathway, and it recruits additional proteins to form multiprotein complexes capable of activating downstream NF-κB inflammatory signaling pathway. Ubiquitin-proteasome system (UPS) plays a crucial role in various protein degradations, such as TRAF6, leading to inhibitory effects on inflammatory response and immunologic function. However, whether ubiquitination-dependent TRAF6 degradation can be used as a novel anti-inflammatory drug target still remains to be explored. FMHM, a bioactive natural small molecule compound extracted from Chinese herbal medicine Radix Polygalae, suppressed acute inflammatory response by targeting ubiquitin protein and inducing UPS-dependent TRAF6 degradation mechanism. It was found that FMHM targeted ubiquitin protein via Lys48 site directly induced Lys48 residue-linked polyubiquitination. This promoted Lys48 residue-linked polyubiquitin chain formation on TRAF6, resulting in increased TRAF6 degradation via UPS and inactivation of downstream NF-κB inflammatory pathway. Consequently, FMHM down-regulated inflammatory mediator levels in circulation, protected multiple organs against inflammatory injury in vivo, and prolong the survival of endotoxemia mouse models. Therefore, FMHM can serve as a novel lead compound for the development of TRAF6 scavenging agent via ubiquitination-dependent mode, which represents a promising strategy for treating inflammatory diseases.

DR5‐Cbl‐b/c‐Cbl‐TRAF2 complex inhibits TRAIL‐induced apoptosis by promoting TRAF2‐mediated polyubiquitination of caspase‐8 in gastric cancer cells

“…Because K48‐linked polyubiquitin chains often promote proteasome‐mediated degradation (Zeng et al ., 2015; Zhang et al ., 2016), BGC823 and MGC803 cells were treated with the proteasome inhibitor bortezomib along with TRAIL. As shown in Fig.…”

Isoacteoside, a dihydroxyphenylethyl glycoside, exhibits anti‐inflammatory effects through blocking toll‐like receptor 4 dimerization

“…This experiment revealed that isoacteoside can significantly protect mice and that it is more effective than DEX, a drug used clinically to treat inflammation (Figure B). A efficacy of a higher dose of DEX (7 or 10 mg·kg −1 ) was found to be greater in mice with LPS‐induced endotoxaemia (Rocksen et al , ; Zeng et al , ; Qin et al , ). However, in terms of side effects, only those observed with the lower dosage of DEX (5 mg·kg −1 ) are reasonable and still meet the clinical requirements (Cicarelli et al , ).…”

“…Dexamethasone (DEX, 5 mg·kg −1 , i.p.) was used as positive control because it has a superior anti‐inflammatory effect (Zeng et al , ; Qin et al , ) and has been used in a clinical study to treat an endotoxic shock (Zhang et al , ). The survival rate was monitored continuously for 132 h. After 132 h, the remaining mice were killed by cervical dislocation under ether anaesthesia.…”

Highly Selective Activation of Heat Shock Protein 70 by Allosteric Regulation Provides an Insight into Efficient Neuroinflammation Inhibition

“…The sequences of the PCR primers for each gene are described in Supplementary Table 2. The relative transcriptional level of target genes was calculated by the 2 − ΔΔCT method with GAPDH as a normalizing gene ( Zeng et al, 2015 ).…”