biostudies-literatureUnknownFang TBasic and Applied Basic Research Foundation of Guangdong ProvinceNational Natural Science Foundation of ChinaLysosome-targeting degradation technologies have emerged as a promising therapeutic strategy for the selective depletion of target extracellular and cell-surface proteins by harnessing a cell-surface effector protein such as lysosome-targeting receptors (LTRs) or transmembrane E3 ligases that direct lysosomal degradation. We recently developed a lysosome-targeting degradation platform termed signal-mediated lysosome-targeting chimeras (SignalTACs) that functions independently of an LTR or E3 ligase; these are engineered fusion proteins comprising a target binder, a cell-penetrating peptide (CPP), and a lysosomal sorting signal motif (P1). Herein, we present the next-generation SignalTACs containing a single endocytic signal that bypasses the need for a CPP. We demonstrate that the fusion wChemical sciencehttps://www.ebi.ac.uk/biostudies/studies/S-EPMC11459673biostudies-literatureLysosome-targeting chimeras containing an endocytic signaling motif trigger endocytosis and lysosomal degradation of cell-surface proteins.PMC11459673821737232024A15150104322022A1515011964Zheng ZFang TZhang YYun CMa JCai XLi NfalseLysosome-targeting chimeras containing an endocytic signaling motif trigger endocytosis and lysosomal degradation of cell-surface proteins.Lysosome-targeting degradation technologies have emerged as a promising therapeutic strategy for the selective depletion of target extracellular and cell-surface proteins by harnessing a cell-surface effector protein such as lysosome-targeting receptors (LTRs) or transmembrane E3 ligases that direct lysosomal degradation. We recently developed a lysosome-targeting degradation platform termed signal-mediated lysosome-targeting chimeras (SignalTACs) that functions independently of an LTR or E3 ligase; these are engineered fusion proteins comprising a target binder, a cell-penetrating peptide (CPP), and a lysosomal sorting signal motif (P1). Herein, we present the next-generation SignalTACs containing a single endocytic signal that bypasses the need for a CPP. We demonstrate that the fusion w2024-01-01T00:00:00Z2024 Oct2025-04-05T09:12:22.914Z2025-04-05T09:12:22.914ZS-EPMC114596733939138310.1039/d4sc05093b