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Peli1 impairs microglial A? phagocytosis through promoting C/EBP? degradation.


ABSTRACT: Amyloid-? (A?) accumulation in the brain is a hallmark of Alzheimer's disease (AD) pathology. However, the molecular mechanism controlling microglial A? 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 A? was then impaired, and therefore Peli1 depletion suppressed the A? deposition in the brains of 5×FAD mice. Mechanistic characterizations indicated that Peli1 directly targeted CCAAT/enhancer-binding protein (C/EBP)?, a major transcription factor responsible for the transcription of scavenger receptor CD36. Peli1 functioned as a direct E3 ubiquitin ligase of C/EBP? and mediated its ubiquitination-induced degradation. Consequently, loss of Peli1 increased the protein levels of C/EBP? 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.

SUBMITTER: Xu J 

PROVIDER: S-EPMC7561136 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Xu Jing J   Yu Tao T   Pietronigro Enrica Caterina EC   Yuan Jia J   Arioli Jessica J   Pei Yifei Y   Luo Xuan X   Ye Jialin J   Constantin Gabriela G   Mao Chaoming C   Xiao Yichuan Y  

PLoS biology 20201005 10


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  ...[more]

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