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

Ada Ndoja1, Rohit Reja2, Seung-Hye Lee3

  • 1Department of Physiological Chemistry, Genentech, South San Francisco, CA 94080, USA.

Cell
|August 16, 2020
PubMed

Insights

COP1 normally suppresses harmful gene activity in microglia, crucial cells in neurodegeneration like Alzheimer's disease. Its absence causes the buildup of c/EBPβ, worsening neuroinflammation and tau pathology.

Area of Science:

  • Neuroscience
  • Immunology
  • Genetics

Background:

  • Microglia, the brain's immune cells, are implicated in neurodegenerative diseases like Alzheimer's disease (AD).
  • The transcription factor CCAAT/enhancer binding protein beta (c/EBPβ) promotes inflammation in microglia and is elevated in AD.
  • Mechanisms controlling detrimental microglial gene expression are not fully understood.

Purpose of the Study:

  • To investigate the role of the ubiquitin ligase COP1 (RFWD2) in regulating microglial gene expression, specifically focusing on c/EBPβ.
  • To determine the impact of COP1 deficiency on microglial pro-inflammatory responses and neurotoxicity.
  • To elucidate COP1's function in microglial contribution to neurodegeneration.

Main Methods:

  • Post-translational regulation of c/EBPβ by COP1 was examined in microglia.
  • Microglia-neuronal co-cultures were used to assess neurotoxicity, with antibody blocking to identify mediators.
  • Gene expression analysis and a mouse model of tau-mediated neurodegeneration were employed to study the effects of COP1 deficiency and Cebpb allele loss.

Main Results:

  • COP1 regulates c/EBPβ protein levels in microglia.
  • COP1 deficiency leads to c/EBPβ accumulation, driving a pro-inflammatory and neurotoxic gene program mediated primarily by complement.
  • Loss of one Cebpb allele mitigated the pro-inflammatory phenotype.
  • COP1-deficient microglia exacerbated tau-mediated neurodegeneration in vivo.

Conclusions:

  • COP1 acts as a crucial suppressor of pathogenic c/EBPβ-dependent gene expression programs in microglia.
  • Targeting the COP1-c/EBPβ axis may offer therapeutic strategies for neurodegenerative diseases driven by microglial activation.
Keywords:
C1qCOP1Tauc/EBPβmicroglianeuroinflammation

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