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Neuroinflammation inhibition by small-molecule targeting USP7 noncatalytic domain for neurodegenerative disease therapy.
Zhang, Xiao-Wen; Feng, Na; Liu, Yan-Chen; Guo, Qiang; Wang, Jing-Kang; Bai, Yi-Zhen; Ye, Xiao-Ming; Yang, Zhuo; Yang, Heng; Liu, Yang; Yang, Mi-Mi; Wang, Yan-Hang; Shi, Xiao-Meng; Liu, Dan; Tu, Peng-Fei; Zeng, Ke-Wu.
Afiliación
  • Zhang XW; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
  • Feng N; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
  • Liu YC; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
  • Guo Q; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
  • Wang JK; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
  • Bai YZ; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
  • Ye XM; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
  • Yang Z; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
  • Yang H; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
  • Liu Y; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
  • Yang MM; Department of Toxicology, School of Public Health, Peking University, Beijing 100191, China.
  • Wang YH; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
  • Shi XM; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
  • Liu D; Proteomics Laboratory, Medical and Healthy Analytical Center, Peking University Health Science Center, Beijing 100191, China.
  • Tu PF; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
  • Zeng KW; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Sci Adv ; 8(32): eabo0789, 2022 08 12.
Article en En | MEDLINE | ID: mdl-35947662
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, Cys576, in a unique noncatalytic HUBL domain. By selectively modifying Cys576, 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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedades Neurodegenerativas / Ubiquitina Tiolesterasa Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Sci Adv Año: 2022 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedades Neurodegenerativas / Ubiquitina Tiolesterasa Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Sci Adv Año: 2022 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos