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

• DOI: 10.1038/srep14715
• Publication Date: 2015-10-01T08:53:36Z
• Authors: Ke-Wu Zeng; Li-Xi Liao; Hai-Ning Lv; Fang-Jiao Song; Qian Yu; Xin Dong; Jun Li; Yong Jiang; Peng-Fei Tu
• Keywords: Inflammation; Lipopolysaccharides; TNF Receptor-Associated Factor 6; 0301 basic medicine; Biological Products; Anti-Inflammatory Agents; NF-kappa B; Nitric Oxide; Article; Endotoxemia; Cell Line; 3. Good health; Toll-Like Receptor 4; Disease Models, Animal; Mice; 03 medical and health sciences; Myeloid Differentiation Factor 88; Proteolysis; Animals; Cytokines; Inflammation Mediators; Drugs, Chinese Herbal; Protein Binding; Signal Transduction

AbstractTNF 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.