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<p>Lysosome-targeting chimeras specifically degrade membrane/extracellular proteins with the specificity and potency highly dependent on the expression pattern and kinetics of lysosome-targeting receptors. Here we describe an endosome-phagophore linking assembly (EPLA), which is constructed by attaching a specific ligand for a protein of interest (POI) to an endosome surface-anchored phagophore-targeting peptide (ES-PTP) that consists of a pH-low insertion peptide and a phagophore-binding element. EPLAs degrade proteins by binding with POIs, being internalized into endosomes, inserting endosome membrane, anchoring the phagophore-targeting moiety onto endosome surface, and then triggering the spatial proximity of endosomes to phagophores. We show the modularity and generality of the EPLA technology by degrading membrane-bound PD-L1, RAGE, GRP94, PSMA, ICAM-1, p32, VCAM-1 and LRP1, and extracellular amyloid-β and tau. Our results establish a technology platform for autophagic degradation of the membrane/extracellular POIs, which may have broad implications for biochemical research and clinical therapeutics.</p>

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Endosome-phagophore linking assemblies for the degradation of membrane/extracellular proteins

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月22日

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  • Pan Wang,
  • Hang Sun,
  • Pei An,
  • Puxian Tang,
  • Qiao Liu,
  • Zini Tang,
  • Taiyong Lv,
  • Jianqing Ruan,
  • Xuechu Zhen,
  • Liang Han

摘要

Lysosome-targeting chimeras specifically degrade membrane/extracellular proteins with the specificity and potency highly dependent on the expression pattern and kinetics of lysosome-targeting receptors. Here we describe an endosome-phagophore linking assembly (EPLA), which is constructed by attaching a specific ligand for a protein of interest (POI) to an endosome surface-anchored phagophore-targeting peptide (ES-PTP) that consists of a pH-low insertion peptide and a phagophore-binding element. EPLAs degrade proteins by binding with POIs, being internalized into endosomes, inserting endosome membrane, anchoring the phagophore-targeting moiety onto endosome surface, and then triggering the spatial proximity of endosomes to phagophores. We show the modularity and generality of the EPLA technology by degrading membrane-bound PD-L1, RAGE, GRP94, PSMA, ICAM-1, p32, VCAM-1 and LRP1, and extracellular amyloid-β and tau. Our results establish a technology platform for autophagic degradation of the membrane/extracellular POIs, which may have broad implications for biochemical research and clinical therapeutics.