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Lysosome-targeting chimaeras for degradation of extracellular proteins

Author

Listed:
  • Steven M. Banik

    (Stanford University)

  • Kayvon Pedram

    (Stanford University)

  • Simon Wisnovsky

    (Stanford University)

  • Green Ahn

    (Stanford University)

  • Nicholas M. Riley

    (Stanford University)

  • Carolyn R. Bertozzi

    (Stanford University
    Howard Hughes Medical Institute)

Abstract

The majority of therapies that target individual proteins rely on specific activity-modulating interactions with the target protein—for example, enzyme inhibition or ligand blocking. However, several major classes of therapeutically relevant proteins have unknown or inaccessible activity profiles and so cannot be targeted by such strategies. Protein-degradation platforms such as proteolysis-targeting chimaeras (PROTACs)1,2 and others (for example, dTAGs3, Trim-Away4, chaperone-mediated autophagy targeting5 and SNIPERs6) have been developed for proteins that are typically difficult to target; however, these methods involve the manipulation of intracellular protein degradation machinery and are therefore fundamentally limited to proteins that contain cytosolic domains to which ligands can bind and recruit the requisite cellular components. Extracellular and membrane-associated proteins—the products of 40% of all protein-encoding genes7—are key agents in cancer, ageing-related diseases and autoimmune disorders8, and so a general strategy to selectively degrade these proteins has the potential to improve human health. Here we establish the targeted degradation of extracellular and membrane-associated proteins using conjugates that bind both a cell-surface lysosome-shuttling receptor and the extracellular domain of a target protein. These initial lysosome-targeting chimaeras, which we term LYTACs, consist of a small molecule or antibody fused to chemically synthesized glycopeptide ligands that are agonists of the cation-independent mannose-6-phosphate receptor (CI-M6PR). We use LYTACs to develop a CRISPR interference screen that reveals the biochemical pathway for CI-M6PR-mediated cargo internalization in cell lines, and uncover the exocyst complex as a previously unidentified—but essential—component of this pathway. We demonstrate the scope of this platform through the degradation of therapeutically relevant proteins, including apolipoprotein E4, epidermal growth factor receptor, CD71 and programmed death-ligand 1. Our results establish a modular strategy for directing secreted and membrane proteins for lysosomal degradation, with broad implications for biochemical research and for therapeutics.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:nature:v:584:y:2020:i:7820:d:10.1038_s41586-020-2545-9
    DOI: 10.1038/s41586-020-2545-9
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    Citations

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    Cited by:

    1. Shasha Yao & Yi Wang & Qian Tang & Yujie Yin & Yu Geng & Lei Xu & Shifu Liang & Jiajia Xiang & Jiaqi Fan & Jianbin Tang & Jian Liu & Shiqun Shao & Youqing Shen, 2024. "A plug-and-play monofunctional platform for targeted degradation of extracellular proteins and vesicles," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Chang Hoon Ji & Hee Yeon Kim & Min Ju Lee & Ah Jung Heo & Daniel Youngjae Park & Sungsu Lim & Seulgi Shin & Srinivasrao Ganipisetti & Woo Seung Yang & Chang An Jung & Kun Young Kim & Eun Hye Jeong & S, 2022. "The AUTOTAC chemical biology platform for targeted protein degradation via the autophagy-lysosome system," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Yaxian Zhou & Chunrong Li & Xuankun Chen & Yuan Zhao & Yaxian Liao & Penghsuan Huang & Wenxin Wu & Nicholas S. Nieto & Lingjun Li & Weiping Tang, 2024. "Development of folate receptor targeting chimeras for cancer selective degradation of extracellular proteins," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    4. Harim I. Won & Samuel Zinga & Olga Kandror & Tatos Akopian & Ian D. Wolf & Jessica T. P. Schweber & Ernst W. Schmid & Michael C. Chao & Maya Waldor & Eric J. Rubin & Junhao Zhu, 2024. "Targeted protein degradation in mycobacteria uncovers antibacterial effects and potentiates antibiotic efficacy," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    5. Arthur Fischbach & Angela Johns & Kara L. Schneider & Xinxin Hao & Peter Tessarz & Thomas Nyström, 2023. "Artificial Hsp104-mediated systems for re-localizing protein aggregates," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    6. Zachary R. Crook & Gregory P. Sevilla & Pamela Young & Emily J. Girard & Tinh-Doan Phi & Monique L. Howard & Jason Price & James M. Olson & Natalie W. Nairn, 2024. "CYpHER: catalytic extracellular targeted protein degradation with high potency and durable effect," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    7. Dan Liu & Jin Yan & Fang Ma & Jingmei Wang & Siqi Yan & Wangxiao He, 2024. "Reinvigoration of cytotoxic T lymphocytes in microsatellite instability-high colon adenocarcinoma through lysosomal degradation of PD-L1," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    8. 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.
    9. Jing Gao & Bo Hou & Qiwen Zhu & Lei Yang & Xingyu Jiang & Zhifeng Zou & Xutong Li & Tianfeng Xu & Mingyue Zheng & Yi-Hung Chen & Zhiai Xu & Huixiong Xu & Haijun Yu, 2022. "Engineered bioorthogonal POLY-PROTAC nanoparticles for tumour-specific protein degradation and precise cancer therapy," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    10. Jean M. Etersque & Iris K. Lee & Nitika Sharma & Kexiang Xu & Andrew Ruff & Justin D. Northrup & Swarbhanu Sarkar & Tommy Nguyen & Richard Lauman & George M. Burslem & Mark A. Sellmyer, 2023. "Regulation of eDHFR-tagged proteins with trimethoprim PROTACs," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    11. Lukas Junk & Volker M. Schmiedel & Somraj Guha & Katharina Fischel & Peter Greb & Kristin Vill & Violetta Krisilia & Lasse Geelen & Klaus Rumpel & Parvinder Kaur & Ramya V. Krishnamurthy & Shridhar Na, 2024. "Homo-BacPROTAC-induced degradation of ClpC1 as a strategy against drug-resistant mycobacteria," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    12. Maik Müller & Fabienne Gräbnitz & Niculò Barandun & Yang Shen & Fabian Wendt & Sebastian N. Steiner & Yannik Severin & Stefan U. Vetterli & Milon Mondal & James R. Prudent & Raphael Hofmann & Marc Oos, 2021. "Light-mediated discovery of surfaceome nanoscale organization and intercellular receptor interaction networks," Nature Communications, Nature, vol. 12(1), pages 1-17, December.

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