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
  • 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: [email protected].
  • 8. Department of Physiological Chemistry, Genentech, South San Francisco, CA 94080, USA. Electronic address: [email protected].
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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