SMARCB1 Promotes Ubiquitination and Degradation of NR4A3 via Direct Interaction Driven by ROS in Vascular Endothelial Cell Injury.
SMARCB1 Promotes Ubiquitination and Degradation of NR4A3 via Direct Interaction Driven by ROS in Vascular Endothelial Cell Injury.
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SMARCB1 在血管内皮细胞损伤中通过 ROS 驱动的直接相互作用促进 NR4A3 泛素化和降解。
DOI：
10.1155/2020/2048210
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发表时间：
2020
影响因子：
--
通讯作者：
Yin W
中科院分区：
文献类型：
--
作者：
Lu B;Zhu Z;Sheng L;Li Y;Yang Y;Chen Y;Xue D;Zhou Y;Cai W;Chen C;Wei C;Xu D;Yan M;Lin S;Yan G;Yin W
核受体亚家族4A组成员3（NR4A3）可保护血管内皮细胞（VEC）免受缺氧应激，其表达主要在转录水平受到调控。然而，NR4A3在蛋白质水平的调控机制在很大程度上尚不明确。在此，我们报道在氧糖剥夺后复氧（OGD - R）诱导的VEC损伤中，NR4A3蛋白丰度大幅下降，而抗氧化类固醇TRIOL的使用可显著阻止这种下降。此外，给予TRIOL后，食蟹猴急性低压缺氧诱导的NR4A3显著改善以及肺内皮屏障高通透性的减轻也有目共睹。在OGD - R条件下，活性氧（ROS）的过量产生会降低VEC中NR4A3蛋白的丰度，而TRIOL和N - 乙酰半胱氨酸（NAC）可逆转这一现象。TRIOL通过抑制泛素化以及泛素蛋白酶体系统（UPS）介导的降解，而非促进其转录，以剂量依赖的方式提高NR4A3蛋白水平。通过酵母双杂交筛选，我们进一步确定了NR4A3与SWI/SNF相关的基质相关、肌动蛋白依赖的染色质调节因子B亚家族成员1（SMARCB1）之间的相互作用，且这种相互作用需要NR4A3的DNA结合结构域。敲低SMARCB1可减少NR4A3的泛素化和降解，这表明这种相互作用具有促泛素化作用，且在OGD - R诱导的VEC损伤中，ROS会增强这种作用。总之，我们的研究首次揭示了由ROS驱动的SMARCB1介导的NR4A3蛋白降解的翻译后调控，这有助于进一步理解VEC在病理条件下NR4A3介导的促生存通路的调控受损情况。
Nuclear receptor subfamily 4 group A member 3 (NR4A3) protects the vascular endothelial cell (VEC) against hypoxia stress, whose expression is primarily reported to be governed at a transcriptional level. However, the regulation of NR4A3 in the protein level is largely unknown. Here, we report that NR4A3 protein abundance is decreased immensely in VEC injury induced by reoxygenation after oxygen-glucose deprivation (OGD-R), which is significantly blocked by the administration of the antioxidative steroid TRIOL. Moreover, the notable improvement of NR4A3 and the alleviation of pulmonary endothelial barrier hyperpermeability induced by acute hypobaric hypoxia in cynomolgus monkeys are also observed after TRIOL administration. The overproduction of reactive oxygen species (ROS) decreases NR4A3 protein abundance in VEC under OGD-R condition, which is reversed by TRIOL and N-acetylcysteine (NAC). TRIOL dose-dependently increases the NR4A3 protein level by inhibiting ubiquitination and ubiquitin proteasome system- (UPS-) mediated degradation rather than promoting its transcription. Using yeast two-hybrid screening, we further identify the interaction between NR4A3 and SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1), and the DNA-binding domain of NR4A3 is required for this interaction. Knockdown of SMARCB1 reduces ubiquitination and degradation of NR4A3, suggesting the proubiquitylation effect of this interaction which is enhanced by ROS in VEC injury induced by OGD-R. In summary, our study here for the first time reveals a posttranslational regulation in SMARCB1-mediated NR4A3 protein degradation which is driven by ROS, providing further understanding of the impaired regulation of NR4A3-mediated prosurvival pathways under pathological condition in VEC.
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