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

生物 小胶质细胞 泛素连接酶 神经炎症 神经退行性变 细胞生物学 泛素 神经毒性 基因敲除 分子生物学 炎症 免疫学 遗传学 化学 基因 医学 病理 有机化学 疾病 毒性
作者
Ada Ndoja,Rohit Reja,Seung-Hye Lee,Joshua D. Webster,Hai Ngu,Christopher M. Rose,Donald S. Kirkpatrick,Zora Modrušan,Ying-Jiun Jasmine Chen,Debra L. Dugger,Vineela Gandham,Luke Xie,Kim Newton,Vishva M. Dixit
出处
期刊:Cell [Cell Press]
卷期号:182 (5): 1156-1169.e12 被引量:150
标识
DOI:10.1016/j.cell.2020.07.011
摘要

•Ubiquitin ligase COP1 promotes proteasomal degradation of c/EBPβ•Loss of COP1 triggers a pro-inflammatory gene expression program in microglia•COP1-deficient microglia exhibit c/EBPβ- and C1q-dependent neurotoxicity•COP1-deficient microglia exacerbate Tau-driven pathology in mice SummaryDysregulated 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. 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.
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