Nedd8 modification of Cullin-5 regulates lipopolysaccharide-induced acute lung injury
Nedd8 modification of Cullin-5 regulates lipopolysaccharide-induced acute lung injury
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Cullin-5 的 Nedd8 修饰调节脂多糖诱导的急性肺损伤
DOI：
10.1152/ajplung.00410.2016
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发表时间：
2017
影响因子：
4.9
通讯作者：
Ye Richard D.
中科院分区：
文献类型：
--
作者：
Zhu Ziyan;Sun Lei;Hao Rui;Jiang Hongchao;Qian Feng;Ye Richard D.
肺部感染是急性肺损伤（ALI）的主要原因，有效的治疗方法有限。肿瘤坏死因子受体相关因子6（TRAF 6）是调节Toll样受体（TLR）的重要衔接子。我们最近确定Cullin-5（Cul-5）作为TRAF 6多聚泛素化调节的重要组成部分，但其在ALI中的生理意义尚未探讨。在这项研究中，我们研究了Cul-5在调节ALI中的潜在作用，使用小鼠接受LPS的肺内滴注。我们观察到，与野生型小鼠相比，Cul-5缺陷型小鼠表现出减少的肺损伤，如组织学分析、肺泡中性粒细胞浸润和肺液体积聚所证明的。此外，支气管肺泡灌洗液和肺组织中的炎性细胞因子表达在LPS处理的Cul-5缺陷小鼠中也显著降低。有趣的是，在LPS攻击的野生型小鼠中，Cul-5+/−而不是Cul-5+/+巨噬细胞的腹膜内过继转移减弱了中性粒细胞的募集、肺泡炎症和屏障功能的丧失。最后，我们证明了LPS暴露后Cul-5 neddylation诱导Cul-5和TRAF 6相互作用，从而诱导TFAR 6多聚泛素化，导致NF-κB活化和促炎细胞因子的产生。我们的数据显示，神经前体细胞表达的Cul-5的发育下调蛋白8（Nedd 8）修饰对于其与TRAF 6的相互作用和LPS诱导的ALI中TLR 4-TRAF 6信号通路的激活是必需的，这是可以探索用于治疗干预的特征。
Lung infections are major causes of acute lung injury (ALI), with limited effective treatment available. Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an essential adaptor regulating Toll-like receptors (TLRs). We recently identified Cullin-5 (Cul-5) as a prominent component in the regulation of TRAF6 polyubiquitination, but its physiological significance in ALI has not been explored. In this study, we investigated the potential role of Cul-5 in regulating ALI using mice receiving intratracheal instillation of LPS. We observed that Cul-5-deficient mice displayed reduced lung injury compared with wild-type mice as evidenced by histological analysis, alveolar neutrophil infiltration, and lung liquid accumulation. In addition, inflammatory cytokine expression in bronchoalveolar lavage fluid and lung tissue was also markedly reduced in LPS-treated Cul-5-deficient mice. Interestingly, intratracheal adoptive transfer ofCul-5+/−but notCul-5+/+macrophages attenuated neutrophil recruitment, alveolar inflammation, and loss of barrier function in LPS-challenged wild-type mice. Finally, we demonstrated that Cul-5 neddylation following LPS exposure induced Cul-5 and TRAF6 interaction and, thereby, TFAR6 polyubiquitination, leading to NF-κB activation and generation of proinflammatory cytokines. Our data show that neural precursor cell expressed developmentally downregulated protein 8 (Nedd8) modification of Cul-5 is required for its interaction with TRAF6 and activation of the TLR4-TRAF6 signaling pathway in LPS-induced ALI, a feature that may be explored for therapeutic intervention.