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泛素连接酶COP1通过降解小胶质细胞c/EBPβ来抑制神经炎症
作者:小柯机器人 发布时间:2020/8/14 18:55:32

美国基因泰克公司Vishva M. Dixit和Kim Newton课题组合作探明,泛素连接酶COP1通过降解小胶质细胞中的转录因子CCAAT /增强子结合蛋白β(c /EBPβ)来抑制神经炎症。2020年8月13日,《细胞》在线发表了这一成果。

研究人员发现小胶质细胞中c /EBPβ的表达受泛素连接酶COP1(也称为RFWD2)翻译后修饰的调控。在缺少COP1的情况下,c /EBPβ迅速积累并诱导促炎和神经退行性相关基因开启,这在小胶质细胞-神经元共培养物中神经毒性增加的情况下得到了验证。抗体阻断研究表明,神经毒性几乎完全是由补体造成的。

值得注意的是,Cebpb单等位基因缺失阻止了促炎表型。在活性小胶质细胞起有害作用的小鼠模型中缺乏COP1的小胶质细胞显著加速了tau介导的神经变性。因此,COP1是小胶质细胞中致病性c /EBPβ依赖基因表达的重要抑制因子。

据了解,小胶质细胞失调与包括阿尔茨海默氏病(AD)在内的神经变性密切相关,但调控致病性小胶质细胞基因表达的机制仍知之甚少。c /EBPβ调控小胶质细胞中的促炎基因的表达,并且其表达量在AD中上调。

附:英文原文

Title: Ubiquitin Ligase COP1 Suppresses Neuroinflammation by Degrading c/EBPβ in Microglia

Author: Ada Ndoja, Rohit Reja, Seung-Hye Lee, Joshua D. Webster, Hai Ngu, Christopher M. Rose, Donald S. Kirkpatrick, Zora Modrusan, Ying-Jiun Jasmine Chen, Debra L. Dugger, Vineela Gandham, Luke Xie, Kim Newton, Vishva M. Dixit

Issue&Volume: 2020-08-13

Abstract: Dysregulated microglia are intimately involved in neurodegeneration, including Alzheimer’s disease (AD) pathogenesis, but the mechanisms controlling pathogenic microglial gene expression remain poorly understood. The transcription factor CCAAT/enhancer binding protein beta (c/EBPβ) regulates pro-inflammatory genes in microglia and is upregulated in AD. We show expression of c/EBPβ in microglia is regulated post-translationally by the ubiquitin ligase COP1 (also called RFWD2). In the absence of COP1, c/EBPβ accumulates rapidly and drives a potent pro-inflammatory and neurodegeneration-related gene program, evidenced by increased neurotoxicity in microglia-neuronal co-cultures. Antibody blocking studies reveal that neurotoxicity is almost entirely attributable to complement. Remarkably, loss of a single allele of Cebpb prevented the pro-inflammatory phenotype. COP1-deficient microglia markedly accelerated tau-mediated neurodegeneration in a mouse model where activated microglia play a deleterious role. Thus, COP1 is an important suppressor of pathogenic c/EBPβ-dependent gene expression programs in microglia.

DOI: 10.1016/j.cell.2020.07.011

Source: https://www.cell.com/cell/fulltext/S0092-8674(20)30876-X

期刊信息
Cell:《细胞》,创刊于1974年。隶属于细胞出版社,最新IF:36.216
官方网址:https://www.cell.com/