The Robo4-TRAF7 complex suppresses endothelial hyperpermeability in inflammation
The Robo4-TRAF7 complex suppresses endothelial hyperpermeability in inflammation
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DOI：
10.1242/jcs.220228
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发表时间：
2019-01-01
影响因子：
4
通讯作者：
Okada, Yoshiaki
中科院分区：
文献类型：
--
作者：
Shirakura, Keisuke;Ishiba, Ryosuke;Okada, Yoshiaki
环形引导受体 4 (Robo4) 是一种内皮细胞特异性受体，可稳定病理性血管生成中的脉管系统。尽管 Robo4 已被证明可以抑制血管生成过程中血管内皮生长因子 (VEGF) 诱导的血管通透性过高，但 Robo4 在炎症中的作用仍知之甚少。在这项研究中，我们研究了 Robo4 在炎症期间血管通透性过高中的作用。使用 Robo4(-/-) 小鼠的内毒素血症模型显示死亡率和血管渗漏增加。在内皮细胞中，Robo4 通过稳定细胞连接处的 VE-钙粘蛋白来抑制肿瘤坏死因子 a (TNF α) 诱导的通透性过高，缺失分析显示 Robo4 的 C 末端参与了这种抑制。通过结合和定位测定，我们证明在内皮细胞中，Robo4 通过与 Robo4 C 末端的相互作用与 TNF 受体相关因子 7 (TRAF7) 结合。对有或没有 Robo4 表达的 TRAF7 的功能获得和丧失的研究表明，TRAF7 是 Robo4 介导的通透性过高抑制所必需的。综上所述，我们的结果表明 Robo4-TRAF7 复合物是炎症通透性过高的新型负调节因子。我们建议将此复合物作为未来预防炎症性疾病的潜在目标。
Roundabout guidance receptor 4 (Robo4) is an endothelial cellspecific receptor that stabilizes the vasculature in pathological angiogenesis. Although Robo4 has been shown to suppress vascular hyperpermeability induced by vascular endothelial growth factor (VEGF) in angiogenesis, the role of Robo4 in inflammation is poorly understood. In this study, we investigated the role of Robo4 in vascular hyperpermeability during inflammation. Endotoxemia models using Robo4(-/-) mice showed increased mortality and vascular leakage. In endothelial cells, Robo4 suppressed tumor necrosis factor a (TNF alpha)-induced hyperpermeability by stabilizing VE-cadherin at cell junctions, and deletion assays revealed that the C-terminus of Robo4 was involved in this suppression. Through binding and localization assays, we demonstrated that in endothelial cells, Robo4 binds to TNF receptor-associated factor 7 (TRAF7) through interaction with the C-terminus of Robo4. Gain- and loss-offunction studies of TRAF7 with or without Robo4 expression showed that TRAF7 is required for Robo4-mediated suppression of hyperpermeability. Taken together, our results demonstrate that the Robo4-TRAF7 complex is a novel negative regulator of inflammatory hyperpermeability. We propose this complex as a potential future target for protection against inflammatory diseases.