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.
Section of General Pathology, Department of Medicine, University of Verona, Verona, Italy.
PLoS Biol. 2020 Oct 5;18(10):e3000837. doi: 10.1371/journal.pbio.3000837. eCollection 2020 Oct.
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.
淀粉样蛋白-β（Aβ）在大脑中的积累是阿尔茨海默病（AD）病理学的标志。然而，控制小胶质细胞 Aβ吞噬作用的分子机制还知之甚少。在这里，我们发现 E3 泛素连接酶 Pellino 1（Peli1）在 AD 样 5 种家族性 AD（5×FAD）小鼠的小胶质细胞中被诱导，其 Aβ的吞噬效率随后受损，因此 Peli1 耗竭抑制了 5×FAD 小鼠大脑中的 Aβ沉积。机制特征表明，Peli1 直接靶向 CCAAT/增强子结合蛋白（C/EBP）β，C/EBPβ 是负责清道夫受体 CD36 转录的主要转录因子。Peli1 作为 C/EBPβ 的直接 E3 泛素连接酶，介导其泛素化诱导的降解。因此，Peli1 的缺失增加了 C/EBPβ 的蛋白水平和 CD36 的表达，从而促进了小胶质细胞的吞噬能力。总之，我们的研究结果确立了 Peli1 作为小胶质细胞吞噬作用的关键调节剂，并强调通过靶向 Peli1 治疗小胶质细胞介导的神经疾病具有治疗潜力。
