Peli1 impairs microglial Aβ phagocytosis through promoting C/EBPβ degradation

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.