Neuroinflammation is a fundamental contributor to progressive neuronal damage, which arouses a heightened interest in neurodegenerative disease therapy. Ubiquitin-specific protease 7 (USP7) has a crucial role in regulating protein stability in multiple biological processes; however, the potential role of USP7 in neurodegenerative progression is poorly understood. Here, we discover the natural small molecule eupalinolide B (EB), which targets USP7 to inhibit microglia activation. Cocrystal structure reveals a previously undisclosed covalent allosteric site, Cys 576 , in a unique noncatalytic HUBL domain. By selectively modifying Cys 576 , EB allosterically inhibits USP7 to cause a ubiquitination-dependent degradation of Keap1. Keap1 function loss further results in an Nrf2-dependent transcription activation of anti-neuroinflammation genes in microglia. In vivo, pharmacological USP7 inhibition attenuates microglia activation and resultant neuron injury, thereby notably improving behavioral deficits in dementia and Parkinson’s disease mouse models. Collectively, our findings provide an attractive future direction for neurodegenerative disease therapy by inhibiting microglia-mediated neuroinflammation by targeting USP7.

中文翻译：

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针对 USP7 非催化结构域的小分子抑制神经退行性疾病治疗的神经炎症

神经炎症是进行性神经元损伤的根本原因，这引起了人们对神经退行性疾病治疗的高度关注。泛素特异性蛋白酶 7 (USP7) 在调节多种生物过程中的蛋白质稳定性方面起着至关重要的作用；然而，人们对 USP7 在神经退行性进展中的潜在作用知之甚少。在这里，我们发现了天然小分子 eupalinolide B (EB)，它靶向 USP7 以抑制小胶质细胞激活。共晶结构揭示了一个以前未公开的共价变构位点 Cys576，在独特的非催化 HUBL 域中。通过选择性地修饰 Cys576, EB 变构抑制 USP7 导致 Keap1 泛素化依赖性降解。Keap1 功能丧失进一步导致小胶质细胞中抗神经炎症基因的 Nrf2 依赖性转录激活。在体内，药理学 USP7 抑制减弱小胶质细胞激活和由此产生的神经元损伤，从而显着改善痴呆和帕金森病小鼠模型的行为缺陷。总的来说，我们的研究结果通过靶向 USP7 抑制小胶质细胞介导的神经炎症，为神经退行性疾病治疗提供了一个有吸引力的未来方向。