Influenza A virus infection of vascular endothelial cells induces GSK-3β-mediated β-catenin degradation in adherens junctions, with a resultant increase in membrane permeability.
Influenza A virus infection of vascular endothelial cells induces GSK-3β-mediated β-catenin degradation in adherens junctions, with a resultant increase in membrane permeability.
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DOI：
10.1007/s00705-014-2270-5
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发表时间：
2015-01
影响因子：
2.7
通讯作者：
Kido, H.
中科院分区：
文献类型：
--
作者：
Hiyoshi, M.;Indalao, I. L.;Yano, M.;Yamane, K.;Takahashi, E.;Kido, H.
多器官功能衰竭伴血管通透性增高是季节性流感病毒肺炎和流感相关脑病进展的最终结局，在高致病性禽流感病毒感染中也很常见。然而，流感病毒感染引起血管内皮细胞高通透性的确切分子机制仍不清楚。我们研究了甲型流感病毒（IAV）/波多黎各/8/34（PR 8）（H1N1）感染的人脐静脉内皮细胞通透性增高的机制。β-catenin的水平，血管内皮细胞-钙粘蛋白细胞粘附复合物的关键调控成分，在感染28小时期间显着下降，与跨内皮电阻测量的血管通透性增加。蛋白酶体抑制剂Lactacystin（2 μM）可抑制β-连环蛋白水平的降低。由于糖原合成酶激酶（GSK）-3β对β-catenin的N-末端磷酸化是蛋白酶体依赖性降解的起始步骤，因此我们检测了RNA干扰对内皮细胞中GSK-3β抑制的影响。在GSK-3β-敲低细胞中，IAV感染诱导的β-catenin降解被显著抑制，并且用重组β-catenin转染细胞显著抑制IAV诱导的高通透性。这些发现表明IAV感染诱导粘附连接复合体中GSK-3β介导的β-连环蛋白降解并诱导血管通透性过高。IAV感染后β-连环蛋白降解和GSK-3β活化的体外发现在感染过程中从第0天到第6天在感染IAV PR 8的小鼠的肺中得到证实。这些结果表明，GSK-3β介导的粘附连接中的β-catenin降解是严重流感中血管通透性过高的关键机制之一。
Multiorgan failure with vascular hyperpermeability is the final outcome in the progression of seasonal influenza virus pneumonia and influenza-associated encephalopathy, and it is also common in infection with highly pathogenic avian influenza virus. However, the precise molecular mechanism by which influenza virus infection causes vascular endothelial cell hyperpermeability remains poorly defined. We investigated the mechanisms of hyperpermeability of human umbilical vein endothelial cells infected with influenza A virus (IAV)/Puerto Rico/8/34 (PR8) (H1N1). The levels of β-catenin, a key regulatory component of the vascular endothelial-cadherin cell adhesion complex, were markedly decreased during infection for 28 h, with increments of vascular hyperpermeability measured by transendothelial electrical resistance. Lactacystin (at 2 μM), a proteasome inhibitor, inhibited the decrease in β-catenin levels. Since the N-terminal phosphorylation of β-catenin by glycogen synthase kinase (GSK)-3β is the initiation step of proteasome-dependent degradation, we examined the effects of GSK-3β suppression by RNA interference in endothelial cells. IAV-infection-induced β-catenin degradation was significantly inhibited in GSK-3β-knockdown cells, and transfection of cells with recombinant β-catenin significantly suppressed IAV-induced hyperpermeability. These findings suggest that IAV infection induces GSK-3β-mediated β-catenin degradation in the adherens junctional complexes and induces vascular hyperpermeability. The in vitro findings of β-catenin degradation and activation of GSK-3β after IAV infection were confirmed in lungs of mice infected with IAV PR8 during the course of infection from day 0 to day 6. These results suggest that GSK-3β-mediated β-catenin degradation in adherens junctions is one of the key mechanisms of vascular hyperpermeability in severe influenza.
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影响因子：
3.2
作者：
Nakamuta, Shinichi;Endo, Hiroshi;Kido, Hiroshi
通讯作者：
Kido, Hiroshi
影响因子：
2.4
作者：
Perkins, LEL;Swayne, DE
通讯作者：
Swayne, DE
DOI：
10.1152/ajpheart.01337.2006
发表时间：
2007-06-01
影响因子：
4.8
作者：
Childs, Ed W.;Tharakan, Binu;Cao, Xiaobo
通讯作者：
Cao, Xiaobo
影响因子：
3.7
作者：
Chowell G;Echevarría-Zuno S;Viboud C;Simonsen L;Miller MA;Fernández-Gárate I;González-Bonilla C;Borja-Aburto VH
通讯作者：
Borja-Aburto VH
影响因子：
3.7
作者：
Le, TQ;Kawachi, M;Kido, H
通讯作者：
Kido, H