TRIM14 promotes endothelial activation via activating NF-κB signaling pathway
TRIM14 promotes endothelial activation via activating NF-κB signaling pathway
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TRIM14 通过激活 NF-kappa B 信号通路促进内皮活化
DOI：
10.1093/jmcb/mjz040
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发表时间：
2020-03-01
影响因子：
5.5
通讯作者：
Fu, Mingui
中科院分区：
文献类型：
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作者：
Huang, Xuan;Li, Yong;Fu, Mingui
促炎细胞因子激活内皮细胞与动脉粥样硬化和其他血管疾病的发病机制密切相关。然而，控制内皮激活的分子机制尚未完全了解。在这里，我们将 TRIM14 确定为通过激活 NF-kappa B 信号通路来调节内皮细胞激活的新正调节因子。 TRIM14 在人血管内皮细胞 (EC) 中高表达，并由 TNF-α、IL-1β 和 LPS 等炎症刺激显着诱导。 TRIM14 的过表达显着增加了活化 EC 中粘附分子（如 VCAM-1、ICAM-1、E-选择素）和细胞因子（如 CCL2、IL-8、CXCL-1 和 TNF-α）的表达，从而促进单核细胞与 EC 的粘附。相反，TRIM14 的敲除对内皮激活具有相反的作用。在 TNF-α 刺激下，TRIM14 通过直接与 NEMO 结合而被招募至 IKK 复合物，并促进 I kappa B α 和 p65 的磷酸化，这取决于其 K63 连接的泛素化。同时，p65可以直接结合人TRIM14基因的启动子区域并控制其mRNA转录。最后，与正常动脉相比，小鼠和人类动脉粥样硬化斑块中的 TRIM14 蛋白水平显着上调。综上所述，这些结果表明 TRIM14-NF-kappa B 形成正反馈环路以增强 EC 激活，TRIM14 可能是动脉粥样硬化等血管炎症性疾病的潜在治疗靶点。
Endothelial activation by proinflammatory cytokines is closely associated to the pathogenesis of atherosclerosis and other vascular diseases; however, the molecular mechanisms controlling endothelial activation are not fully understood. Here we identify TRIM14 as a new positive regulator of endothelial activation via activating NF-kappa B signal pathway. TRIM14 is highly expressed in human vascular endothelial cells (ECs) and markedly induced by inflammatory stimuli such as TNF-alpha, IL-1 beta, and LPS. Overexpression of TRIM14 significantly increased the expression of adhesion molecules such as VCAM-1, ICAM-1, E-selectin, and cytokines such as CCL2, IL-8, CXCL-1, and TNF-alpha in activated ECs and by which it facilitated monocyte adhesion to ECs. Conversely, knockdown of TRIM14 has opposite effect on endothelial activation. Upon TNF-alpha stimulation, TRIM14 is recruited to IKK complex via directly binding to NEMO and promotes the phosphorylation of I kappa B alpha and p65, which is dependent on its K63-linked ubiquitination. Meanwhile, p65 can directly bind to the promoter regions of human TRIM14 gene and control itsmRNA transcription. Finally, TRIM14 protein level is significantly upregulated in mouse and human atheroma compared to normal arteries. Taken together, these results indicate that TRIM14-NF-kappa B forms a positive feedback loop to enhance EC activation and TRIM14 may be a potential therapeutic target for vascular inflammatory diseases such as atherosclerosis.