Ubiquitin Ligase COP1 Suppresses Neuroinflammation by Degrading c/EBPβ in Microglia.
Alzheimer Disease
/ metabolism
Animals
CCAAT-Enhancer-Binding Protein-beta
/ metabolism
Cell Line
Coculture Techniques
/ methods
Female
Gene Expression
/ physiology
Gene Expression Regulation
/ physiology
HEK293 Cells
Humans
Inflammation
/ metabolism
Ligases
/ metabolism
Male
Mice
Mice, Inbred C57BL
Microglia
/ metabolism
Neurons
/ metabolism
Ubiquitin
/ genetics
Ubiquitin-Protein Ligases
/ metabolism
C1q
COP1
Tau
c/EBPβ
microglia
neuroinflammation
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
03 09 2020
03 09 2020
Historique:
received:
07
04
2020
revised:
09
06
2020
accepted:
10
07
2020
pubmed:
17
8
2020
medline:
8
5
2021
entrez:
16
8
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32795415
pii: S0092-8674(20)30876-X
doi: 10.1016/j.cell.2020.07.011
pii:
doi:
Substances chimiques
CCAAT-Enhancer-Binding Protein-beta
0
CEBPB protein, human
0
Ubiquitin
0
COP1 protein, human
EC 2.3.2.27
Ubiquitin-Protein Ligases
EC 2.3.2.27
Ligases
EC 6.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1156-1169.e12Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests All authors were employees of Genentech.