Ubiquitin-activating enzyme E1 inhibitor PYR41 attenuates angiotensin II-induced activation of dendritic cells via the IBa/NF-B and MKP1/ERK/STAT1 pathways
Ubiquitin-activating enzyme E1 inhibitor PYR41 attenuates angiotensin II-induced activation of dendritic cells via the IBa/NF-B and MKP1/ERK/STAT1 pathways
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泛素激活酶 E1 抑制剂 PYR41 通过 IBa/NF-B 和 MKP1/ERK/STAT1 途径减弱血管紧张素 II 诱导的树突状细胞激活
DOI：
10.1111/imm.12255
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发表时间：
2014-06-01
期刊：
影响因子：
6.4
通讯作者：
Du, Jie
中科院分区：
文献类型：
--
作者：
Chen, Chen;Meng, Yan;Du, Jie
树突状细胞(DC)的激活是启动免疫反应所必需的。血管紧张素II(AngII)可促进DC的成熟和活化，但其作用机制尚不清楚。泛素激活酶(E1Uba1)是泛素化过程中常见的第一步，它决定了修饰后的蛋白质是否最终被蛋白酶体降解。本研究旨在探讨E1在血管紧张素Ⅱ诱导树突状细胞活化中的作用及其机制。首先，我们发现血管紧张素转换酶刺激显著上调树突状细胞的E1表达。此外，AngII处理可显著诱导DC的表型成熟、细胞因子的分泌和免疫刺激能力。而小分子抑制剂4[4-(5-硝基-呋喃-2-亚甲基)-3，5-二氧基吡唑烷-1-基]-苯甲酸乙酯(PYR41)对E1的抑制作用明显减弱。在机制上，PYR41可显著降低K63相关的肿瘤坏死因子受体相关因子6和核因子B基本调节物的泛素化，抑制核因子B抑制物和丝裂原活化蛋白激酶磷酸酶1的蛋白酶体降解，从而导致血管紧张素Ⅱ诱导的DC核因子B、细胞外信号调节激酶1/2以及信号转导和转录激活因子1信号通路的激活。综上所述，我们的结果表明，E1在血管紧张素Ⅱ诱导的DC激活中具有新的作用，抑制E1的活性可能是DC介导的自身免疫性疾病的潜在治疗靶点。
The activation of dendritic cells (DCs) is necessary to initiate immune responses. Angiotensin II (AngII) can enhance the maturation and activation of DCs, but the mechanisms are still unclear. Ubiquitin-activating enzyme (E1/Uba1) is the common first step in ubiquitylation, which decides whether or not the modified protein is ultimately degraded by the proteasome. This study aimed to investigate the role of E1 in AngII-induced activation of DCs and the underlying mechanisms. First, we showed that AngII stimulation significantly up-regulated E1 expression in DCs. Moreover, AngII treatment markedly induced phenotypic maturation, the secretion of cytokines and the immunostimulatory capacity of DCs. In contrast, inhibition of E1 by a small molecule inhibitor, 4[4-(5-nitro-furan-2-ylmethylene)-3, 5-dioxo-pyrazolidin-1-yl]-benzoic acid ethyl ester (PYR41), markedly attenuated these effects. Mechanistically, PYR41 treatment markedly decreased K63-linked ubiquitination of tumour necrosis factor receptor-associated factor 6 and nuclear factor-B essential modulator, inhibited proteasomal degradation of nuclear factor-B inhibitor and mitogen-activated protein kinase phosphatase 1 thereby resulting in activation of nuclear factor-B, extracellular signal-regulated kinase 1/2 and signal transducer and activator of transcription 1 signalling pathways in DCs induced by AngII. Taken together, our results demonstrate a novel role of E1 in AngII-induced activation of DCs, and inhibition of E1 activity might be a potential therapeutic target for DC-mediated autoimmune diseases.