Peli1 impairs microglial Aβ phagocytosis through promoting C/EBPβ degradation

  • PLoS Biol. 2020 Oct 5;18(10):e3000837. doi: 10.1371/journal.pbio.3000837.
Jing Xu  1 ,  Tao Yu  1 ,  Enrica Caterina Pietronigro  2 ,  Jia Yuan  1 ,  Jessica Arioli  2 ,  Yifei Pei  1 ,  Xuan Luo  3 ,  Jialin Ye  1 ,  Gabriela Constantin  2 ,  Chaoming Mao  3 ,  Yichuan Xiao  1
Affiliations
  • 1. CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 2. Section of General Pathology, Department of Medicine, University of Verona, Verona, Italy.
  • 3. Department of Nuclear Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, China.
PMID: 33017390 DOI: 10.1371/journal.pbio.3000837
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.

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