E3 Ligase FBXW2 Is a New Therapeutic Target in Obesity and Atherosclerosis,Advanced Science

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E3 Ligase FBXW2 Is a New Therapeutic Target in Obesity and Atherosclerosis
Advanced Science ( IF 14.3 ) Pub Date : 2020-08-26 , DOI: 10.1002/advs.202001800
Cheng Wang _{1,

2} , Wenjing Xu ₁ , Yuelin Chao ₃ , Minglu Liang ₁ , Fengxiao Zhang ₁ , Kai Huang ₁

Affiliation

Chronic low‐grade inflammation orchestrated by macrophages plays a critical role in metabolic chronic diseases, like obesity and atherosclerosis. However, the underlying mechanism remains to be elucidated. Here, the E3 ubiquitin ligase F‐box/WD Repeat‐Containing Protein 2 (FBXW2), the substrate‐binding subunit of E3 ubiquitin ligase SCF (a complex of FBXW2, SKP1, and cullin‐1), as an inflammatory mediator in macrophages, is identified. Myeloid‐specific FBXW2 gene deficiency improves both obesity‐associated with insulin resistance and atherosclerosis in murine models. The beneficial effects by FBXW2 knockout are accompanied by decreased proinflammatory responses and macrophage infiltration in the microenvironment. Mechanistically, it is identified that KH‐type splicing regulatory protein (KSRP) is a new bona fide ubiquitin substrate of SCF^FBXW2. Inhibition of KSRP prevents FBXW2‐deficient macrophages from exerting a protective effect on inflammatory reactions, insulin resistance and plaque formation. Furthermore, it is demonstrated that the C‐terminus (P3) of FBXW2 competitively ablates the function of FBXW2 in KSRP degradation and serves as an effective inhibitor of obesity and atherogenesis progression. Thus, the data strongly suggest that SCF^FBXW2 is an important mediator in the context of metabolic diseases. The development of FBXW2 (P3)‐mimicking inhibitors and small‐molecular drugs specifically abrogating KSRP ubiquitination‐dependent inflammatory responses are viable approaches for obesity and atherosclerosis treatment.

中文翻译：

E3 连接酶 FBXW2 是肥胖和动脉粥样硬化的新治疗靶点

由巨噬细胞精心策划的慢性低度炎症在肥胖和动脉粥样硬化等代谢性慢性疾病中发挥着关键作用。然而，其根本机制仍有待阐明。在这里，E3 泛素连接酶 F-box/WD 重复含有蛋白 2 (FBXW2)，E3 泛素连接酶 SCF 的底物结合亚基（FBXW2、SKP1 和 cullin-1 的复合物），作为巨噬细胞中的炎症介质，被识别。骨髓特异性 FBXW2 基因缺陷可改善小鼠模型中与胰岛素抵抗相关的肥胖和动脉粥样硬化。 FBXW2 敲除的有益效果伴随着微环境中促炎症反应和巨噬细胞浸润的减少。从机制上讲，KH型剪接调节蛋白（KSRP）被认为是SCF ^FBXW2的一种新的真正泛素底物。抑制 KSRP 可阻止 FBXW2 缺陷型巨噬细胞对炎症反应、胰岛素抵抗和斑块形成发挥保护作用。此外，事实证明，FBXW2 的 C 末端 (P3) 竞争性地消除 FBXW2 在 KSRP 降解中的功能，并作为肥胖和动脉粥样硬化进展的有效抑制剂。因此，数据强烈表明 SCF ^FBXW2是代谢疾病中的重要介质。开发 FBXW2 (P3) 模拟抑制剂和专门消除 KSRP 泛素化依赖性炎症反应的小分子药物是治疗肥胖和动脉粥样硬化的可行方法。

更新日期：2020-10-22

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