bims-lycede Biomed News
on Lysosome-dependent cell death
Issue of 2025–02–09
two papers selected by
Sofía Peralta, Universidad Nacional de Cuyo
  1. Glucuronidase-Instructed Glycopeptide Self-Assembly for Selective Killing of Cancer Cells through Lysosomal Membrane Permeabilization.
  2. Endoplasmic reticulum (ER) protein degradation by ER-associated degradation and ER-phagy.
  1. Angew Chem Int Ed Engl. 2025 Feb 05. e202420596
    Glucuronidase-Instructed Glycopeptide Self-Assembly for Selective Killing of Cancer Cells through Lysosomal Membrane Permeabilization.
    Zhongxin Xu, Changdong He, Xinyu Li, Lu Huang, Bo Cheng, Suwei Dong.
      Current cancer treatments face significant challenges, including limited tumor specificity and drug resistance. Enzyme-instructed supramolecular peptide assembly targeting lysosomes offers a promising strategy to address these issues; however, self-assembling units that withstand lysosomal conditions are still scarce. In this study, we present a versatile glycopeptide incorporating glucuronic acid and glucose that undergoes glucuronidase-triggered self-assembly to form nanofibers, leading to lysosomal membrane permeabilization (LMP) in cancer cells. Mechanistic studies revealed that in glucuronidase-overexpressing HepG2 cells, glycopeptide assembly induces cytoskeletal disruption and apoptosis. The involvement of carbohydrate-binding receptor in enhancing the cellular entry of glycopeptides and improving proteolytic stability highlights the importance of glycan modification. Notably, combining this glycopeptide with cisplatin or adriamycin results in synergistic cytotoxicity, including in drug-resistant cancer lines. These findings establish a novel, LMP-inducing glycopeptide scaffold for developing targeted approaches for cancer treatment.
    Keywords:  Cytotoxicity; glucuronidase; glycopeptides; lysosomal membrane permeabilization; self-assembly
    DOI:  https://doi.org/10.1002/anie.202420596
  2. Trends Cell Biol. 2025 Feb 04. pii: S0962-8924(25)00002-9. [Epub ahead of print]
    Endoplasmic reticulum (ER) protein degradation by ER-associated degradation and ER-phagy.
    Shuangcheng Alivia Wu, Zexin Jason Li, Ling Qi.
      Protein misfolding and aggregation in the endoplasmic reticulum (ER) have been causally linked to a variety of human diseases. Two key pathways for eliminating misfolded proteins and aggregates in the ER are ER-associated degradation (ERAD) and ER-phagy, respectively. While both pathways have been well characterized biochemically, our understanding of their physiological relevance and significance remains limited. In recent years, significant advances have been made, including the generation and characterization of various knockout and knockin mouse models, the identification of human disease-associated or -causing variants, and insights into the coordination between ERAD and autophagy in physiological contexts. In this review, we summarize these advancements, highlighting the key roles of a highly conserved suppressor of lin-12-like-hydroxymethyl glutaryl-coenzyme A reductase degradation 1 (SEL1L-HRD1) protein complex of ERAD and ER-phagy in health and disease.
    Keywords:  ER-associated protein degradation (ERAD); ER-phagy; ER-phagy receptors; SEL1L-HRD1; disease variants; substrates
    DOI:  https://doi.org/10.1016/j.tcb.2025.01.002
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