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A co-assembly platform engaging macrophage scavenger receptor A for lysosome-targeting protein degradation

Author

Listed:
  • Qian Wang

    (Peking University
    Peking University
    Peking University)

  • Xingyue Yang

    (Peking University
    Peking University
    Peking University)

  • Ruixin Yuan

    (Peking University
    Peking University
    Peking University)

  • Ao Shen

    (Peking University
    Peking University
    Peking University)

  • Pushu Wang

    (Peking University
    Peking University
    Peking University)

  • Haoting Li

    (Peking University
    Peking University
    Peking University)

  • Jun Zhang

    (Peking University
    Peking University
    Peking University)

  • Chao Tian

    (Peking University)

  • Zhujun Jiang

    (Peking University)

  • Wenzhe Li

    (Peking University)

  • Suwei Dong

    (Peking University
    Peking University
    Peking University)

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.

Suggested Citation

  • Qian Wang & Xingyue Yang & Ruixin Yuan & Ao Shen & Pushu Wang & Haoting Li & Jun Zhang & Chao Tian & Zhujun Jiang & Wenzhe Li & Suwei Dong, 2024. "A co-assembly platform engaging macrophage scavenger receptor A for lysosome-targeting protein degradation," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46130-0
    DOI: 10.1038/s41467-024-46130-0
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    References listed on IDEAS

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    1. Steven M. Banik & Kayvon Pedram & Simon Wisnovsky & Green Ahn & Nicholas M. Riley & Carolyn R. Bertozzi, 2020. "Lysosome-targeting chimaeras for degradation of extracellular proteins," Nature, Nature, vol. 584(7820), pages 291-297, August.
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