VE钙粘蛋白
泛素
钙粘蛋白
细胞生物学
血管通透性
炎症
内皮
突变体
内吞作用
生物
组胺
体内
化学
免疫学
细胞
生物化学
基因
遗传学
内分泌学
作者
Markus Wilkens,Leonie Holtermann,A Stahl,Rebekka I. Stegmeyer,Astrid F. Nottebaum,Dietmar Vestweber
标识
DOI:10.1038/s44319-024-00221-7
摘要
Abstract VE-cadherin is a major component of the cell adhesion machinery which provides integrity and plasticity of the barrier function of endothelial junctions. Here, we analyze whether ubiquitination of VE-cadherin is involved in the regulation of the endothelial barrier in inflammation in vivo. We show that histamine and thrombin stimulate ubiquitination of VE-cadherin in HUVEC, which is completely blocked if the two lysine residues K626 and K633 are replaced by arginine. Similarly, these mutations block histamine-induced endocytosis of VE-cadherin. We describe two knock-in mouse lines with endogenous VE-cadherin being replaced by either a VE-cadherin K626/633R or a VE-cadherin KallR mutant, where all seven lysine residues are mutated. Mutant mice are viable, healthy and fertile with normal expression levels of junctional VE-cadherin. Histamine- or LPS-induced vascular permeability in the skin or lung of both of these mutant mice are clearly and similarly reduced in comparison to WT mice. Additionally, we detect a role of K626/633 for lysosomal targeting. Collectively, our findings identify ubiquitination of VE-cadherin as important for the induction of vascular permeability in the inflamed skin and lung.
科研通智能强力驱动
Strongly Powered by AbleSci AI