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

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 and Qi Chen ()
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Jingjing Ben: Nanjing Medical University
Bin Jiang: Nanjing Medical University
Dongdong Wang: Nanjing Medical University
Qingling Liu: Nanjing Medical University
Yongjing Zhang: Nanjing Medical University
Yu Qi: Nanjing Medical University
Xing Tong: Nanjing Medical University
Lili Chen: Nanjing Medical University
Xianzhong Liu: Nanjing Medical University
Yan Zhang: Nanjing Medical University
Xudong Zhu: Nanjing Medical University
Xiaoyu Li: Nanjing Medical University
Hanwen Zhang: Nanjing Medical University
Hui Bai: Nanjing Medical University
Qing Yang: Nanjing Medical University
Junqing Ma: Nanjing Medical University
Erik A. C. Wiemer: Erasmus University Medical Center
Yong Xu: Nanjing Medical University
Qi Chen: Nanjing Medical University

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract Macrophage-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.

Date: 2019
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DOI: 10.1038/s41467-019-09588-x

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