A co-assembly platform engaging macrophage scavenger receptor A for lysosome-targeting protein degradation
Abstract Targeted degradation of proteins has emerged as a powerful method for modulating protein homeostasis. Identification of suitable degraders is essential for achieving effective protein degradation. Here, we present a non-covalent degrader construction strategy, based on a modular supramolecu...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-46130-0 |
| _version_ | 1797274063323791360 |
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| author | Qian Wang Xingyue Yang Ruixin Yuan Ao Shen Pushu Wang Haoting Li Jun Zhang Chao Tian Zhujun Jiang Wenzhe Li Suwei Dong |
| author_facet | Qian Wang Xingyue Yang Ruixin Yuan Ao Shen Pushu Wang Haoting Li Jun Zhang Chao Tian Zhujun Jiang Wenzhe Li Suwei Dong |
| author_sort | Qian Wang |
| collection | DOAJ |
| description | Abstract Targeted degradation of proteins has emerged as a powerful method for modulating protein homeostasis. Identification of suitable degraders is essential for achieving effective protein degradation. Here, we present a non-covalent degrader construction strategy, based on a modular supramolecular co-assembly system consisting of two self-assembling peptide ligands that bind cell membrane receptors and the protein of interest simultaneously, resulting in targeted protein degradation. The developed lysosome-targeting co-assemblies (LYTACAs) can induce lysosomal degradation of extracellular protein IL-17A and membrane protein PD-L1 in several scavenger receptor A-expressing cell lines. The IL-17A-degrading co-assembly has been applied in an imiquimod-induced psoriasis mouse model, where it decreases IL-17A levels in the skin lesion and alleviates psoriasis-like inflammation. Extending to asialoglycoprotein receptor-related protein degradation, LYTACAs have demonstrated the versatility and potential in streamlining degraders for extracellular and membrane proteins. |
| first_indexed | 2024-03-07T14:53:01Z |
| format | Article |
| id | doaj.art-e365b84b830841a3b63505cc355e9eca |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-07T14:53:01Z |
| publishDate | 2024-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-e365b84b830841a3b63505cc355e9eca2024-03-05T19:35:18ZengNature PortfolioNature Communications2041-17232024-02-0115111410.1038/s41467-024-46130-0A co-assembly platform engaging macrophage scavenger receptor A for lysosome-targeting protein degradationQian Wang0Xingyue Yang1Ruixin Yuan2Ao Shen3Pushu Wang4Haoting Li5Jun Zhang6Chao Tian7Zhujun Jiang8Wenzhe Li9Suwei Dong10State Key Laboratory of Natural and Biomimetic Drugs, Peking UniversityState Key Laboratory of Natural and Biomimetic Drugs, Peking UniversityState Key Laboratory of Natural and Biomimetic Drugs, Peking UniversityState Key Laboratory of Natural and Biomimetic Drugs, Peking UniversityState Key Laboratory of Natural and Biomimetic Drugs, Peking UniversityState Key Laboratory of Natural and Biomimetic Drugs, Peking UniversityState Key Laboratory of Natural and Biomimetic Drugs, Peking UniversityDepartment of Chemical Biology, School of Pharmaceutical Sciences, Peking UniversityState Key Laboratory of Natural and Biomimetic Drugs, Peking UniversityState Key Laboratory of Natural and Biomimetic Drugs, Peking UniversityState Key Laboratory of Natural and Biomimetic Drugs, Peking UniversityAbstract Targeted degradation of proteins has emerged as a powerful method for modulating protein homeostasis. Identification of suitable degraders is essential for achieving effective protein degradation. Here, we present a non-covalent degrader construction strategy, based on a modular supramolecular co-assembly system consisting of two self-assembling peptide ligands that bind cell membrane receptors and the protein of interest simultaneously, resulting in targeted protein degradation. The developed lysosome-targeting co-assemblies (LYTACAs) can induce lysosomal degradation of extracellular protein IL-17A and membrane protein PD-L1 in several scavenger receptor A-expressing cell lines. The IL-17A-degrading co-assembly has been applied in an imiquimod-induced psoriasis mouse model, where it decreases IL-17A levels in the skin lesion and alleviates psoriasis-like inflammation. Extending to asialoglycoprotein receptor-related protein degradation, LYTACAs have demonstrated the versatility and potential in streamlining degraders for extracellular and membrane proteins.https://doi.org/10.1038/s41467-024-46130-0 |
| spellingShingle | Qian Wang Xingyue Yang Ruixin Yuan Ao Shen Pushu Wang Haoting Li Jun Zhang Chao Tian Zhujun Jiang Wenzhe Li Suwei Dong A co-assembly platform engaging macrophage scavenger receptor A for lysosome-targeting protein degradation Nature Communications |
| title | A co-assembly platform engaging macrophage scavenger receptor A for lysosome-targeting protein degradation |
| title_full | A co-assembly platform engaging macrophage scavenger receptor A for lysosome-targeting protein degradation |
| title_fullStr | A co-assembly platform engaging macrophage scavenger receptor A for lysosome-targeting protein degradation |
| title_full_unstemmed | A co-assembly platform engaging macrophage scavenger receptor A for lysosome-targeting protein degradation |
| title_short | A co-assembly platform engaging macrophage scavenger receptor A for lysosome-targeting protein degradation |
| title_sort | co assembly platform engaging macrophage scavenger receptor a for lysosome targeting protein degradation |
| url | https://doi.org/10.1038/s41467-024-46130-0 |
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