Major vault protein suppresses obesity and atherosclerosis through inhibiting IKK-NF-κB signaling mediated inflammation.
Jingjing BenBin JiangDongdong WangQingling LiuYongjing ZhangYu QiXing TongLili ChenXianzhong LiuYan ZhangXudong ZhuXiaoyu LiHanwen ZhangHui BaiQing YangJunqing MaErik A C WiemerYong XuQi ChenPublished in: Nature communications (2019)
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.
Keyphrases
- high fat diet induced
- insulin resistance
- signaling pathway
- adipose tissue
- oxidative stress
- low grade
- pi k akt
- high fat diet
- metabolic syndrome
- skeletal muscle
- lps induced
- cardiovascular disease
- polycystic ovary syndrome
- high grade
- type diabetes
- binding protein
- nuclear factor
- transcription factor
- genome wide
- single cell
- acute myeloid leukemia
- bone marrow
- immune response
- amino acid
- cell proliferation
- dna methylation
- physical activity