Department of Pharmacology and Regenerative Medicine and The Center of Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, IL, USA.
AVMBioMed, King of Prussia, PA, USA.
Nat Commun. 2023 Oct 18;14(1):6582. doi: 10.1038/s41467-023-42225-2.
Vascular endothelial cadherin (VE-cadherin) expressed at endothelial adherens junctions (AJs) is vital for vascular integrity and endothelial homeostasis. Here we identify the requirement of the ubiquitin E3-ligase CHFR as a key mechanism of ubiquitylation-dependent degradation of VE-cadherin. CHFR was essential for disrupting the endothelium through control of the VE-cadherin protein expression at AJs. We observe augmented expression of VE-cadherin in endothelial cell (EC)-restricted Chfr knockout (Chfr) mice. We also observe abrogation of LPS-induced degradation of VE-cadherin in Chfr mice, suggesting the pathophysiological relevance of CHFR in regulating the endothelial junctional barrier in inflammation. Lung endothelial barrier breakdown, inflammatory neutrophil extravasation, and mortality induced by LPS were all suppressed in Chfr mice. We find that the transcription factor FoxO1 is a key upstream regulator of CHFR expression. These findings demonstrate the requisite role of the endothelial cell-expressed E3-ligase CHFR in regulating the expression of VE-cadherin, and thereby endothelial junctional barrier integrity.
血管内皮钙黏蛋白 (VE-cadherin) 在血管内皮黏附连接点 (AJs) 上的表达对血管完整性和内皮稳态至关重要。在这里，我们确定了泛素 E3 连接酶 CHFR 的必需性，作为 VE-cadherin 依赖泛素化降解的关键机制。CHFR 通过控制 AJ 处 VE-cadherin 的蛋白表达，对于破坏内皮至关重要。我们观察到内皮细胞 (EC) 特异性 Chfr 敲除 (Chfr) 小鼠中 VE-cadherin 的表达增加。我们还观察到 Chfr 小鼠中 LPS 诱导的 VE-cadherin 降解被阻断，这表明 CHFR 在调节炎症中内皮连接屏障方面具有病理生理学相关性。LPS 诱导的肺内皮屏障破坏、炎症性中性粒细胞渗出和死亡率在 Chfr 小鼠中均受到抑制。我们发现转录因子 FoxO1 是 CHFR 表达的关键上游调节剂。这些发现表明内皮细胞表达的 E3 连接酶 CHFR 在调节 VE-cadherin 的表达及其内皮连接屏障完整性方面具有必需作用。
