beta-Catenin phosphorylation at Y654 and Y142 is crucial for high mobility group box-1 protein-induced pulmonary vascular hyperpermeability
beta-Catenin phosphorylation at Y654 and Y142 is crucial for high mobility group box-1 protein-induced pulmonary vascular hyperpermeability
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Y654 和 Y142 处的 β-连环蛋白磷酸化对于高迁移率族 box-1 蛋白诱导的肺血管通透性过高至关重要
DOI：
10.1016/j.yjmcc.2018.12.012
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发表时间：
2019
影响因子：
5
通讯作者：
Guo Xiaohua
中科院分区：
文献类型：
--
作者：
Weng Jie;Yu Lei;Chen Zhenfeng;Su Haiying;Yu Shengxiang;Zhang Yuanjian;Lei Xiaotian;Chen Lixian;Cui Yun;Huang Qiaobing;Jiang Yong;Guo Xiaohua
目的内皮细胞高通透性是脓毒症所致急性肺损伤的一个特征。黏附连接(AJ)介导的细胞间黏附力和应力纤维驱动的收缩作用力之间的不平衡导致内皮通透性增加。在这里，我们重点研究了β-连环蛋白Y654和Y142磷酸化在HMGB1介导的内皮屏障泄漏中的作用。方法和结果表明，β-连环蛋白Y654和Y142的磷缺乏改善了接受盲肠结扎和穿孔手术的雄性C57小鼠的肺血管功能障碍。体外分析表明，高迁移率族蛋白1(HMGB1)激活了β-连环蛋白Y654和Y142的磷酸化，导致β-连环蛋白易位和黏附连接(AJ)中断以及细胞骨架重排。此外，β-连环蛋白Y654去磷酸化减弱了HMGB1介导的VE-钙粘蛋白/β-连环蛋白的解离，从而部分地阻止了内皮细胞的高通透性。β-连环蛋白Y142去磷酸化可阻断HMGB1诱导的β-连环蛋白和α-连环蛋白的解偶联，抑制细胞骨架重组，从而减轻内皮细胞的高通透性。进一步的研究表明，β-catenin Y654的磷酸化需要RAGE和src来响应HMGB1，而FAK负责HMGB1触发的β-catenin Y142的磷酸化。结论本研究揭示了β-catenin Y654和Y142的磷酸化在HMGB1介导的内皮细胞高通透性中的作用，其机制可能是通过黏附和收缩力量之间的失调。这一结果促进了对脓毒症肺血管高通透性的机制的理解。
ObjectiveEndothelial hyperpermeability is a hallmark of acute lung injury in response to sepsis. The imbalance between adherence junction (AJ) mediated cell-cell adherence forces and stress fiber driven contractile forces contributes to increased endothelial permeability. Here, we spotlight the effects of β-catenin Y654 andY142 phosphorylation on HMGB1-mediated endothelial barrier leakage.Approach and resultsOur results showed that phospho-deficiencies at both β-catenin Y654and Y142ameliorated pulmonary vascular dysfunction in male C57 mice receiving a cecal ligation and puncture operation. In vitro analysis indicated that high mobility group box-1 protein (HMGB1) triggered β-catenin Y654 and Y142 phosphorylation, causing β-catenin translocation and adherence junction (AJ) disruptions as well as cytoskeleton rearrangement. In addition,β-catenin Y654 dephosphorylation attenuated HMGB1-mediated dissociation of VE-cadherin/β-catenin and, hence, partially prevented endothelial hyperpermeability. β-catenin Y142 dephosphorylation abolished HMGB1-induced uncoupling of β-catenin and α-catenin, suppressed cytoskeletal reassembly and, hence, alleviated endothelial hyperpermeability. Further investigation demonstrated that RAGE and Src were required forβ-catenin Y654 phosphorylation in response to HMGB1, while FAK was responsible for HMGB1-triggered β-catenin Y142 phosphorylation.ConclusionsIn sum, this study revealed the role of β-catenin Y654 and Y142 phosphorylation in HMGB1-mediated endothelial hyperpermeability through dysregulation between adherence and contractile forces. This result advances understanding of the mechanisms underlying pulmonary vascular hyperpermeability in sepsis.