Major vault protein suppresses obesity and atherosclerosis through inhibiting IKK–NF-κB signaling mediated inflammation

• DOI: 10.1038/s41467-019-09588-x
• Publication Date: 2019-04-17T10:14:19Z
• Authors: Jingjing Ben; Bin Jiang; Dongdong Wang; Qingling Liu; Yongjing Zhang; Yu Qi; Xing Tong; Lili Chen; Xianzhong Liu; Yan Zhang; Xudong Zhu; Xiaoyu Li; Hanwen Zhang; Hui Bai; Qing Yang; Junqing Ma; Erik A. C. Wiemer; Yong Xu; Qi Chen
• Keywords: Male; 0301 basic medicine; Mice, Knockout, ApoE; Science; Biopsy; Bone Marrow Cells; Diet, High-Fat; Article; Gene Knockout Techniques; Mice; 03 medical and health sciences; SDG 3 - Good Health and Well-being; Animals; Humans; Inflammation; 2. Zero hunger; Macrophages; Q; NF-kappa B; Atherosclerosis; I-kappa B Kinase; Fatty Liver; Mice, Inbred C57BL; Disease Models, Animal; Interleukin-1 Receptor-Associated Kinases; EMC MM-03-86-08; Adipose Tissue; Female

AbstractMacrophage-orchestrated, low-grade chronic inflammation plays a pivotal role in obesity and atherogenesis. However, the underlying regulatory mechanisms remain incompletely understood. Here, we identify major vault protein (MVP), the main component of unique cellular ribonucleoprotein particles, as a suppressor for NF-κB signaling in macrophages. Both global and myeloid-specific MVP gene knockout aggravates high-fat diet induced obesity, insulin resistance, hepatic steatosis and atherosclerosis in mice. The exacerbated metabolic disorders caused by MVP deficiency are accompanied with increased macrophage infiltration and heightened inflammatory responses in the microenvironments. In vitro studies reveal that MVP interacts with TRAF6 preventing its recruitment to IRAK1 and subsequent oligomerization and ubiquitination. Overexpression of MVP and its α-helical domain inhibits the activity of TRAF6 and suppresses macrophage inflammation. Our results demonstrate that macrophage MVP constitutes a key constraint of NF-κB signaling thereby suppressing metabolic diseases.