Cell, 2020-09, Vol.182 (5), p.1156-1169.e12
2020
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Details
- Autor(en) / Beteiligte
- Titel
- Ubiquitin Ligase COP1 Suppresses Neuroinflammation by Degrading c/EBPβ in Microglia
- Ist Teil von
- Cell, 2020-09, Vol.182 (5), p.1156-1169.e12
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2020
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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. [Display omitted] •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 Expression of c/EBPβ, a factor elevated in brains of patients with Alzheimer’s disease, is regulated post-translationally by COP1, an E3 ubiquitin ligase whose loss leads to microglial activation and neurotoxicity.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0092-8674eISSN: 1097-4172DOI: 10.1016/j.cell.2020.07.011Titel-ID: cdi_crossref_primary_10_1016_j_cell_2020_07_011
- Format
- –
- Schlagworte
- Alzheimer Disease - metabolism, Animals, c/EBPβ, C1q, CCAAT-Enhancer-Binding Protein-beta - metabolism, Cell Line, Coculture Techniques - methods, COP1, Female, Gene Expression - physiology, Gene Expression Regulation - physiology, HEK293 Cells, Humans, Inflammation - metabolism, Ligases - metabolism, Male, Mice, Mice, Inbred C57BL, microglia, Microglia - metabolism, neuroinflammation, Neurons - metabolism, Tau, Ubiquitin - genetics, Ubiquitin-Protein Ligases - metabolism