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.

The Emerging Roles of Pellino Family in Pattern Recognition Receptor Signaling

“…Upon trans-activating protein (Tat), Pellino1 induces autophagy, interrupts expression of tight junction protein zonula occludens1 (ZO-1), and increases the permeability of the blood-brain barrier (BBB) by triggering K63-Ub of Beclin1 (76). Pellino1 also impairs microglial amyloid bprotein (Ab) phagocytosis through promoting CCAAT enhancerbinding protein b (C-EBPb) degradation in Alzheimer's disease (AD) (77). In Parkinson's disease, upregulation of Pellino1 by asynuclein leads to the degradation of lysosomal-associated membrane protein-2 (LAMP2) and the buildup of autophagy with decreased autophagy flux by microglial exosomes (78).…”

Research Progress of Targeting Neuro-Immune Inflammation in the Treatment of Alzheimer's Disease

“…PBDML can phagocytose Aβ to reduce the burden of Aβ in the brain, thereby improving cognitive impairment in mice [52]. Xu J et al [53] found that ubiquitin ligase (Peli1) is a key regulator of microglia phagocytosis, and targeting E3 Peli1 can reduce the level of CCAAT/enhancer binding protein (C/EBP) β and CD36 expression, thereby enhancing microglia phagocytosis. Bruton's tyrosine kinase (BTK) is another key regulator of microglia phagocytosis.…”

“…Although a lot of researches have been done in this field in recent years (Table 3, Ref. [40][41][42][43]47,49,51,[53][54][55]58,61,64,65,[68][69][70]75,76,[78][79][80][81][83][84][85][86][87][89][90][91][92][93][94]), many important problems still exist. At present few of these drugs are applied to clinical practice, and many researches have only been tested on animals.…”

Microglia, TREM2, and Therapeutic Methods of Alzheimer’s Disease

“…The pellino-1 (peli1) is a ubiquitin E3 ligase, expressed in many kinds of nerve cells in the mouse brain, and with the highest expression level of microglia [42]. Similarly, Peli1 negatively regulates the ability of phagocytosis of microglia to Aβ, resulting in the inability of clearance of deposition, leading to the deterioration of AD [43].…”