期刊
SCIENCE ADVANCES
卷 8, 期 32, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abo0789
关键词
-
资金
- National Key Research and Development Project [2019YFC1711000, 2019YFC1708902]
- National Natural Science Foundation [81973505, 81773932]
This study discovers a natural small molecule called eupalinolide B (EB) that inhibits USP7 to alleviate symptoms of neurodegenerative diseases. EB selectively modifies the Cys(576) site, inhibiting the activity of USP7 and causing the degradation of Keap1. This leads to the activation of anti-neuroinflammation genes in microglia. The effectiveness of this treatment method is validated in mouse models.
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.
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