APC/Cdh1 targets PECAM-1 for ubiquitination and degradation in endothelial cells
APC/Cdh1 targets PECAM-1 for ubiquitination and degradation in endothelial cells
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APC/Cdh1 靶向 PECAM-1 在内皮细胞中泛素化和降解
DOI：
10.1002/jcp.29156
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发表时间：
2019-09-05
影响因子：
5.6
通讯作者：
Wang, Nanping
中科院分区：
文献类型：
--
作者：
Liu, Jia;Yao, Qinyu;Wang, Nanping
血小板内皮细胞粘附分子-1（PECAM-1）是免疫球蛋白超家族的成员，由造血细胞和内皮细胞（EC）表达。最近的研究表明，PECAM-1起着至关重要的作用，促进EC炎症反应的发展，在扰动流的背景下。然而，控制PECAM-1蛋白稳定性的机制途径在很大程度上仍不清楚。在这里，我们确定PECAM-1作为APC/Cdh 1 E3泛素连接酶的新底物。具体而言，慢病毒介导的Cdh 1耗竭稳定了EC中的PECAM-1。相反，Cdh 1的过表达使PECAM-1不稳定。蛋白酶体抑制剂MG 132阻断Cdh 1介导的PECAM-1降解。此外，Cdh 1以破坏盒依赖性方式促进PECAM-1的K48连接的多聚泛素化。此外，我们证明，与脉动剪切应力（PS）相比，振荡剪切应力降低Cdh 1的表达和PECAM-1的泛素化，从而稳定PECAM-1，以促进EC中的炎症。因此，我们的研究揭示了一种新的机制，通过这种机制，流体流动模式通过Cdh 1依赖的泛素化和随后的PECAM-1降解来调节EC稳态。
Platelet endothelial cell adhesion molecule-1 (PECAM-1) is a member of the immunoglobulin superfamily and is expressed by hematopoietic and endothelial cells (ECs). Recent studies have shown that PECAM-1 plays a crucial role in promoting the development of the EC inflammatory response in the context of disturbed flow. However, the mechanistic pathways that control PECAM-1 protein stability remain largely unclear. Here, we identified PECAM-1 as a novel substrate of the APC/Cdh1 E3 ubiquitin ligase. Specifically, lentivirus-mediated Cdh1 depletion stabilized PECAM-1 in ECs. Conversely, overexpression of Cdh1 destabilized PECAM-1. The proteasome inhibitor MG132 blocked Cdh1-mediated PECAM-1 degradation. In addition, Cdh1 promoted K48-linked polyubiquitination of PECAM-1 in a destruction box-dependent manner. Furthermore, we demonstrated that compared with pulsatile shear stress (PS), oscillatory shear stress decreased the expression of Cdh1 and the ubiquitination of PECAM-1, therefore stabilizing PECAM-1 to promote inflammation in ECs. Hence, our study revealed a novel mechanism by which fluid flow patterns regulate EC homeostasis via Cdh1-dependent ubiquitination and subsequent degradation of PECAM-1.