2. Academic Validation
  3. Ubiquitin Ligase COP1 Suppresses Neuroinflammation by Degrading c/EBPβ in Microglia

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

  • Cell. 2020 Sep 3;182(5):1156-1169.e12. doi: 10.1016/j.cell.2020.07.011.
Ada Ndoja 1,  Rohit Reja 2,  Seung-Hye Lee 3,  Joshua D Webster 4,  Hai Ngu 4,  Christopher M Rose 5,  Donald S Kirkpatrick 5,  Zora Modrusan 5,  Ying-Jiun Jasmine Chen 5,  Debra L Dugger 1,  Vineela Gandham 6,  Luke Xie 6,  Kim Newton 7,  Vishva M Dixit 8
Affiliations

Affiliations

  • 1 Department of Physiological Chemistry, Genentech, South San Francisco, CA 94080, USA.
  • 2 Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080, USA.
  • 3 Department of Neuroscience, Genentech, South San Francisco, CA 94080, USA.
  • 4 Department of Pathology, Genentech, South San Francisco, CA 94080, USA.
  • 5 Department of Microchemistry, Proteomics, Lipidomics and Next Generation Sequencing, Genentech, South San Francisco, CA 94080, USA.
  • 6 Department of Biomedical Imaging, Genentech, South San Francisco, CA 94080, USA.
  • 7 Department of Physiological Chemistry, Genentech, South San Francisco, CA 94080, USA. Electronic address: knewton@gene.com.
  • 8 Department of Physiological Chemistry, Genentech, South San Francisco, CA 94080, USA. Electronic address: dixit@gene.com.
PMID: 32795415 DOI: 10.1016/j.cell.2020.07.011
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.

Keywords

C1q; COP1; Tau; c/EBPβ; microglia; neuroinflammation.

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