Ubiquitin ligase COP1 suppresses microglia-mediated inflammation

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). Ubiquitination of c/EBPß by COP1 targets it for proteasomal degradation. In the absence of COP1, c/EBPß accumulates rapidly and drives a potent pro-inflammatory and ApoE gene-expression 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 elevated ApoE plays a deleterious role. Collectively, these results identify c/EBPß as a potential therapeutic target for inflammation-driven neurodegeneration. Refer to individual Series