| First Author | Ndoja A | Year | 2020 |
| Journal | Cell | Volume | 182 |
| Issue | 5 | Pages | 1156-1169.e12 |
| PubMed ID | 32795415 | Mgi Jnum | J:328941 |
| Mgi Id | MGI:7339309 | Doi | 10.1016/j.cell.2020.07.011 |
| Citation | Ndoja A, et al. (2020) Ubiquitin Ligase COP1 Suppresses Neuroinflammation by Degrading c/EBPbeta in Microglia. Cell 182(5):1156-1169.e12 |
| abstractText | 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/EBPbeta) regulates pro-inflammatory genes in microglia and is upregulated in AD. We show expression of c/EBPbeta in microglia is regulated post-translationally by the ubiquitin ligase COP1 (also called RFWD2). In the absence of COP1, c/EBPbeta 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/EBPbeta-dependent gene expression programs in microglia. |
