Cereblon suppresses the lipopolysaccharide-induced inflammatory response by promoting the ubiquitination and degradation of c-Jun
Cereblon suppresses the lipopolysaccharide-induced inflammatory response by promoting the ubiquitination and degradation of c-Jun
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Cereblon 通过促进 c-Jun 泛素化和降解来抑制脂多糖诱导的炎症反应
DOI：
10.1074/jbc.ra118.002246
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发表时间：
2018
影响因子：
4.8
通讯作者：
Guoqiang Xu
中科院分区：
文献类型：
--
作者：
Jing Yang;Min Huang;Liang Zhou;Xian He;Xiaogang Jiang;Yang Zhang;Guoqiang Xu
慢性炎症与多种人类疾病相关，例如类风湿性关节炎、代谢疾病和神经退行性疾病。因此，减轻由环境刺激诱导的炎症对于疾病预防或治疗是重要的。Cereblon（CRBN）作为cullin-4 RING E3连接酶的底物受体，介导蛋白质泛素化和降解。尽管已经报道CRBN通过其非酶功能减少炎症反应，但其作为E3连接酶的底物受体的作用在介导该过程中没有被探索。在这里，我们使用了定量蛋白质组学方法，发现激活蛋白1（AP-1）复合物的主要成分，c-Jun，在CRBN表达后显著下调。生物化学方法进一步发现CRBN与c-Jun相互作用并部分共定位，并促进c-Jun上Lys 48连接的聚泛素链的形成，增强c-Jun降解。我们进一步揭示，CRBN减弱AP-1复合物的转录活性，并降低几种促炎细胞因子的mRNA表达和蛋白水平。此外，流式细胞术分析表明，CRBN减弱分化的THP-1细胞中脂多糖诱导的细胞凋亡。通过基因操作和药物抑制，我们揭示了CRBN调节脂多糖诱导的炎症反应和凋亡的新分子机制。我们的工作和以前的研究表明，CRBN通过促进或抑制两个关键分子在不同水平的炎症级联反应，通过其作为底物受体的酶功能和其作为蛋白质结合伴侣的非酶功能的泛素化抑制炎症反应。
Chronic inflammation is associated with multiple human disorders, such as rheumatoid arthritis, metabolic diseases, and neurodegenerative diseases. Therefore, alleviation of inflammation induced by environmental stimuli is important for disease prevention or treatment. Cereblon (CRBN) functions as a substrate receptor of the cullin-4 RING E3 ligase to mediate protein ubiquitination and degradation. Although it has been reported that CRBN reduces the inflammatory response through its nonenzymatic function, its role as a substrate receptor of the E3 ligase is not explored in mediating this process. Here we used a quantitative proteomics approach to find that the major component of the activator protein 1 (AP-1) complex, c-Jun, is significantly down-regulated upon CRBN expression. Biochemical approaches further discover that CRBN interacts and partially colocalizes with c-Jun and promotes the formation of Lys48-linked polyubiquitin chains on c-Jun, enhancing c-Jun degradation. We further reveal that CRBN attenuates the transcriptional activity of the AP-1 complex and reduces the mRNA expression and protein level of several pro-inflammatory cytokines. Moreover, flow cytometry analyses show that CRBN attenuates lipopolysaccharide-induced apoptosis in differentiated THP-1 cells. Through genetic manipulation and pharmacological inhibition, we uncover a new molecular mechanism by which CRBN regulates the inflammatory response and apoptosis induced by lipopolysaccharide. Our work and previous studies demonstrate that CRBN suppresses the inflammatory response by promoting or inhibiting the ubiquitination of two key molecules at different levels of the inflammatory cascade through its enzymatic function as a substrate receptor and its nonenzymatic function as a protein binding partner.