Epsin-mediated degradation of IP3R1 fuels atherosclerosis
Epsin-mediated degradation of IP3R1 fuels atherosclerosis
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DOI：
10.1038/s41467-020-17848-4
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发表时间：
2020-08-07
影响因子：
16.6
通讯作者：
Chen, Hong
中科院分区：
文献类型：
--
作者：
Dong, Yunzhou;Lee, Yang;Chen, Hong
内吞衔接蛋白的epsin家族广泛表达，并与蛋白质和脂质相互作用以调节多种细胞功能。然而，epsins在动脉粥样硬化中的作用知之甚少。在这里，我们表明，删除内皮epsin蛋白减少炎症和衰减动脉粥样硬化，使用细胞培养和这种疾病的小鼠模型。在致动脉粥样硬化胆固醇处理的小鼠主动脉内皮细胞中，epsins与泛素化内质网蛋白1，4，5-三磷酸肌醇受体1型（IP 3R 1）相互作用，从而触发该钙释放通道的蛋白酶体降解。Epsins通过这种相互作用加强其降解。内皮IP 3R 1的遗传减少加速动脉粥样硬化，而内皮epsins的缺失稳定IP 3R 1并减轻炎症。在epsin缺陷小鼠中IP 3R 1的减少恢复动脉粥样硬化进展。总之，epsin介导的IP 3R 1降解代表了epsin蛋白以前未发现的生物学作用，并可能为动脉粥样硬化和其他疾病的治疗提供新的治疗靶点。内皮细胞（EC）功能障碍和炎症导致动脉粥样硬化斑块不稳定，增加血栓事件的风险。在这里，作者表明，epsin通过涉及IP 3R 1降解的机制促进EC炎症，并且内皮中epsin的缺失可防止小鼠EC功能障碍和动脉粥样硬化。
The epsin family of endocytic adapter proteins are widely expressed, and interact with both proteins and lipids to regulate a variety of cell functions. However, the role of epsins in atherosclerosis is poorly understood. Here, we show that deletion of endothelial epsin proteins reduces inflammation and attenuates atherosclerosis using both cell culture and mouse models of this disease. In atherogenic cholesterol-treated murine aortic endothelial cells, epsins interact with the ubiquitinated endoplasmic reticulum protein inositol 1,4,5-trisphosphate receptor type 1 (IP3R1), which triggers proteasomal degradation of this calcium release channel. Epsins potentiate its degradation via this interaction. Genetic reduction of endothelial IP3R1 accelerates atherosclerosis, whereas deletion of endothelial epsins stabilizes IP3R1 and mitigates inflammation. Reduction of IP3R1 in epsin-deficient mice restores atherosclerotic progression. Taken together, epsin-mediated degradation of IP3R1 represents a previously undiscovered biological role for epsin proteins and may provide new therapeutic targets for the treatment of atherosclerosis and other diseases. Endothelial cell (EC) dysfunction and inflammation contribute to plaque destabilization in atherosclerosis, increasing the risk of thrombotic events. Here, the authors show that epsin promotes EC inflammation via a mechanism involving IP3R1 degradation, and that deletion of epsin in the endothelium prevents EC dysfunctoin and atherosclerosis in mice.