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Discovery of a molecular glue that enhances UPRmt to restore proteostasis via TRKA-GRB2-EVI1-CRLS1 axis

Li-Feng-Rong Qi, View ORCID ProfileCheng Qian, Shuai Liu, Chao Peng, Mu Zhang, Peng Yang, Ping Wu, Ping Li, View ORCID ProfileXiaojun Xu
doi: https://doi.org/10.1101/2021.02.17.431525
Li-Feng-Rong Qi
1State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009, Nanjing, Jiangsu, China
2Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, 210009, Nanjing, Jiangsu, China
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Cheng Qian
1State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009, Nanjing, Jiangsu, China
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  • ORCID record for Cheng Qian
Shuai Liu
1State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009, Nanjing, Jiangsu, China
2Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, 210009, Nanjing, Jiangsu, China
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Chao Peng
3National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai 201210, China
4Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai, 201204, China
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Mu Zhang
1State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009, Nanjing, Jiangsu, China
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Peng Yang
1State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009, Nanjing, Jiangsu, China
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Ping Wu
3National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai 201210, China
4Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai, 201204, China
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Ping Li
1State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009, Nanjing, Jiangsu, China
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Xiaojun Xu
1State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009, Nanjing, Jiangsu, China
2Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, 210009, Nanjing, Jiangsu, China
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  • ORCID record for Xiaojun Xu
  • For correspondence: liping2004@126.com xiaojunxu2000@163.com
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Abstract

Lowering proteotoxicity is a potentially powerful approach for the treatment of neurological disorders, such as Parkinson’s disease. The unfolded protein response (UPR) is a major mechanism that preserves the network maintaining cellular proteostasis. In the present study, we developed the screening strategy to discover compounds that significantly enhanced the activation of mitochondrial UPR (UPRmt) through increasing cardiolipin content. We identified that ginsenoside Rg3 (Rg3) increased cardiolipin depending on cardiolipin synthase 1 (CRLS1) in both worms and in human neural cells. Using LiP-SMap (limited proteolysis-mass spectrometry) strategy, we identified GRB2 (growth factor receptor bound protein 2) as a direct target of Rg3 in human neural cells. Rg3 enhances the binding between GRB2 and TRKA, that transduces signals via phosphrorylation of ERK. We provide bioinformatic and experimental evidence that EVI1, the critical oncogenic transcriptional regulator in leukemia, binds to CRLS1 promoter region and stimulated CRLS1 expression and subsequently increased cardiolipin content in the presence of Rg3. In a Parkinson’s disease mouse model, Rg3 restores motor function by protecting nigral dopaminergic neurons dependent on Grb2. Our data recapitulate the TRKA-GRB2-EVI1-CRLS1 axis in maintaining proteostasis in Parkinson’s disease via UPRmt.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted February 17, 2021.
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Discovery of a molecular glue that enhances UPRmt to restore proteostasis via TRKA-GRB2-EVI1-CRLS1 axis
Li-Feng-Rong Qi, Cheng Qian, Shuai Liu, Chao Peng, Mu Zhang, Peng Yang, Ping Wu, Ping Li, Xiaojun Xu
bioRxiv 2021.02.17.431525; doi: https://doi.org/10.1101/2021.02.17.431525
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Discovery of a molecular glue that enhances UPRmt to restore proteostasis via TRKA-GRB2-EVI1-CRLS1 axis
Li-Feng-Rong Qi, Cheng Qian, Shuai Liu, Chao Peng, Mu Zhang, Peng Yang, Ping Wu, Ping Li, Xiaojun Xu
bioRxiv 2021.02.17.431525; doi: https://doi.org/10.1101/2021.02.17.431525

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