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

Abstract:

: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.

journal_name

PLoS Biol

journal_title

PLoS biology

authors

Xu J,Yu T,Pietronigro EC,Yuan J,Arioli J,Pei Y,Luo X,Ye J,Constantin G,Mao C,Xiao Y

doi

10.1371/journal.pbio.3000837

subject

Has Abstract

pub_date

2020-10-05 00:00:00

pages

e3000837

issue

10

eissn

1544-9173

issn

1545-7885

pii

PBIOLOGY-D-20-00092

journal_volume

18

pub_type

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