Ubiquitin Ligase COP1 Suppresses Neuroinflammation by Degrading c/EBPß in Microglia.
Cell
; 182(5): 1156-1169.e12, 2020 09 03.
Article
em En
| MEDLINE
| ID: mdl-32795415
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/EBPß) regulates pro-inflammatory genes in microglia and is upregulated in AD. We show expression of c/EBPß in microglia is regulated post-translationally by the ubiquitin ligase COP1 (also called RFWD2). In the absence of COP1, c/EBPß 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/EBPß-dependent gene expression programs in microglia.
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MEDLINE
Assunto principal:
Microglia
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Proteína beta Intensificadora de Ligação a CCAAT
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Ubiquitina
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Ubiquitina-Proteína Ligases
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Ligases
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article