Peli1 impairs microglial Aβ phagocytosis through promoting C/EBPβ degradation.

Autor: Xu, Jing, Yu, Tao, Pietronigro, Enrica Caterina, Yuan, Jia, Arioli, Jessica, Pei, Yifei, Luo, Xuan, Ye, Jialin, Constantin, Gabriela, Mao, Chaoming, Xiao, Yichuan
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Zdroj: PLoS Biology; 10/5/2020, Vol. 18 Issue 10, p1-21, 21p, 1 Color Photograph, 3 Graphs
Abstrakt: Amyloid-β (Aβ) accumulation in the brain is a hallmark of Alzheimer's disease (AD) pathology. However, the molecular mechanism controlling microglial Aβ phagocytosis is poorly understood. Here we found that the E3 ubiquitin ligase Pellino 1 (Peli1) is induced in the microglia of AD-like five familial AD (5×FAD) mice, whose phagocytic efficiency for Aβ was then impaired, and therefore Peli1 depletion suppressed the Aβ deposition in the brains of 5×FAD mice. Mechanistic characterizations indicated that Peli1 directly targeted CCAAT/enhancer-binding protein (C/EBP)β, a major transcription factor responsible for the transcription of scavenger receptor CD36. Peli1 functioned as a direct E3 ubiquitin ligase of C/EBPβ and mediated its ubiquitination-induced degradation. Consequently, loss of Peli1 increased the protein levels of C/EBPβ and the expression of CD36 and thus, promoted the phagocytic ability in microglial cells. Together, our findings established Peli1 as a critical regulator of microglial phagocytosis and highlighted the therapeutic potential by targeting Peli1 for the treatment of microglia-mediated neurological diseases. This study identifies Peli1, an E3 ubiqitin ligase enriched in microglia, as a restraining factor that curtails microglial phagocytosis of the amyloid Aβ. Correspondingly, deletion of Peli1 enhances Aβ phagocytosis and clearance in Alzheimer's disease, implicating Peli1 as a therapeutic target with significant potential for the treatment of microglia-mediated neurological disease. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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