bims-lycede Biomed News
on Lysosome-dependent cell death
Issue of 2024–05–19
eight papers selected by
Sofía Peralta, Universidad Nacional de Cuyo
  1. A delicate decision between repair and degradation of damaged lysosomes.
  2. Acid-assisted self-assembly of pyrene-capped tyrosine ruptures lysosomes to induce cancer cell apoptosis.
  3. Targeting selective autophagy and beyond: From underlying mechanisms to potential therapies.
  4. Lysosome dynamics during human endometrial stromal cells decidualization: effect of para-nonylphenol.
  5. High-fidelity imaging of a tumour-associated lysosomal enzyme with an acceptor engineering-boosted near-infrared fluorescent probe.
  6. Exploring the connections between ER-based lipid metabolism and plasma membrane nanodomain signaling.
  7. Therapeutic antibody engineering for efficient targeted degradation of membrane proteins in lysosomes.
  8. The differential expression patterns of Atg9a and Atg9b in cells of the reproductive organs.
  1. Autophagy. 2024 May 14. 1-2
    A delicate decision between repair and degradation of damaged lysosomes.
    Yuchen Lei, Daniel J Klionsky.
      The destination of a damaged lysosome is either being repaired if the damage is small or degraded through a lysosome-specific macroautophagy/autophagy pathway named lysophagy when the damage is too extensive to repair. Even though previous studies report lumenal glycan exposure during lysosome damage as a signal to trigger lysophagy, it is possibly beneficial for cells to initiate lysophagy earlier than membrane rupture. In a recently published article, Gahlot et al. determined that SPART/SPG20 senses lipid-packing defects and recruits and activates the ubiquitin ligase ITCH, which labels damaged lysosomes with ubiquitin chains to initiate lysophagy.
    Keywords:  ESCRT; lipid-packing defect; lysophagy; lysosome damage; ubiquitination
    DOI:  https://doi.org/10.1080/15548627.2024.2350738
  2. RSC Adv. 2024 May 15. 14(23): 15840-15847
    Acid-assisted self-assembly of pyrene-capped tyrosine ruptures lysosomes to induce cancer cell apoptosis.
    Jing Li, Jiaqi Song, Liang Shao, Xianpeng Zhang, Ziyi Wang, Guanying Li, Jiansheng Wang, Jia Zhang.
      Induced lysosomal membrane permeabilization (LMP) by peptide self-assembly has emerged as an effective platform for lysosome-targeted cancer therapy. In this study, we shift this strategical paradigm and present an innovative approach to LMP induction through amino acid-based self-assembly. Pyrene-capped tyrosine (Py-Tyr), as a proof-of-concept molecule, is designed with acidity-responsive self-assembly. Under acidic conditions (pH 4), Py-Tyr is protonated with reduced charge repulsion, and self-assembles into micrometer-scaled aggregates, which exceed the biological size of lysosomes. Cell experiments showed that Py-Tyr specifically accumulates in lysosomes and induces lysosome rupture, leading to the release of cathepsin B into the cytoplasm for subsequent apoptosis activation in cancer cells. This study capitalizes on the concept of amino acid assembly for efficient LMP induction, providing a simple and versatile platform for precise and effective therapeutic interventions in cancer therapy.
    DOI:  https://doi.org/10.1039/d4ra01328j
  3. J Adv Res. 2024 May 13. pii: S2090-1232(24)00199-1. [Epub ahead of print]
    Targeting selective autophagy and beyond: From underlying mechanisms to potential therapies.
    Wei Ma, Yingying Lu, Xin Jin, Na Lin, Lan Zhang, Yaowen Song.
       BACKGROUND: Autophagy is an evolutionarily conserved turnover process for intracellular substances in eukaryotes, relying on lysosomal (in animals) or vacuolar (in yeast and plants) mechanisms. In the past two decades, emerging evidence suggests that, under specific conditions, autophagy can target particular macromolecules or organelles for degradation, a process termed selective autophagy. Recently, accumulating studies have demonstrated that the abnormality of selective autophagy is closely associated with the occurrence and progression of many human diseases, including neurodegenerative diseases, cancers, metabolic diseases, and cardiovascular diseases.
    AIM OF REVIEW: This review aims at systematically and comprehensively introducing selective autophagy and its role in various diseases, while unravelling the molecular mechanisms of selective autophagy. By providing a theoretical basis for the development of related small-molecule drugs as well as treating related human diseases, this review seeks to contribute to the understanding of selective autophagy and its therapeutic potential.
    KEY SCIENTIFIC CONCEPTS OF REVIEW: In this review, we systematically introduce and dissect the major categories of selective autophagy that have been discovered. We also focus on recent advances in understanding the molecular mechanisms underlying both classical and non-classical selective autophagy. Moreover, the current situation of small-molecule drugs targeting different types of selective autophagy is further summarized, providing valuable insights into the discovery of more candidate small-molecule drugs targeting selective autophagy in the future. On the other hand, we also reveal clinically relevant implementations that are potentially related to selective autophagy, such as predictive approaches and treatments tailored to individual patients.
    Keywords:  Autophagy; Clinically relevant implementation; Human disease; Molecular mechanism; Selective autophagy; Small-molecule drug
    DOI:  https://doi.org/10.1016/j.jare.2024.05.009
  4. Am J Physiol Cell Physiol. 2024 May 13.
    Lysosome dynamics during human endometrial stromal cells decidualization: effect of para-nonylphenol.
    Sofia Passaponti, Camilla Manzan Martins, Laura Cresti, Roberta Romagnoli, Luana Paulesu, Francesca Ietta, Leonardo Ermini.
      During the process of decidualization, the stromal cells of the endometrium change dynamically to create a favorable environment for embryo implantation. Lysosome activity has often been associated with physiological changes in the endometrium during the pre-implantation period and early pregnancy. In this study, the effect of para-nonylphenol (p-NP), an endocrine disruptor, on human immortalized endometrial stromal cells (tHESCs) was investigated. After exposure to p-NP (1 nM and 1 pM), the cells were examined for the decidualization markers Connexin-43, insulin like growth factor binding protein 1 (IGFBP1) and Prolactin. In addition, the effect of p-NP on lysosome biogenesis and exocytosis was investigated by examining the expression and localization of the transcription factor EB (TFEB) and that of the lysosomal-associated membrane protein 1 (LAMP-1). Finally, we evaluated the effect of p-NP on ECM remodeling using a fibronectin assay. Our results showed that p-NP reduced the expression of Prolactin protein, increased the nuclear localization of TFEB, and induced the increase and translocation of the lysosomal protein LAMP-1 to the membrane of tHESCs. The data indicate an impairment of decidualization and suggest an increase in lysosomal biogenesis and exocytosis, which is supported by the higher release of active cathepsin D by tHESCs. Given the importance of cathepsins in the processing and degradation of the ECM during trophoblast invasiveness and migration into the decidua, our results appear to be clear evidence of the negative effects of p-NP on endometrial processes that are fundamental to reproductive success and the establishment of pregnancy.
    Keywords:  Para-Nonylphenol; endocrine disruptor; endometrial decidualization; lysosome biogenesis; lysosome exocytosis
    DOI:  https://doi.org/10.1152/ajpcell.00604.2023
  5. Chem Sci. 2024 May 15. 15(19): 7324-7331
    High-fidelity imaging of a tumour-associated lysosomal enzyme with an acceptor engineering-boosted near-infrared fluorescent probe.
    Bin Feng, Feiyi Chu, Yanpeng Fang, Min Liu, Xueping Feng, Jie Dong, Fei Chen, Wenbin Zeng.
      To facilitate the understanding of the dynamic distribution and activity of lysosomal enzymes, it is highly desirable to develop high-fidelity near-infrared (NIR) activatable fluorescent probes. Here, we propose a general acceptor engineering strategy to construct NIR probes with lysosome-targeting capability. Upon isosteric replacement and additional functionalization, the β-gal-activatable probe OELyso-Gal exhibited excellent lysosome-targeting capability and favorable responsive performance to the enzyme of interest. Notably, the steric hindrance effect from acceptor engineering is modest, which renders the probe unprecedented affinity to enzymes. Upon the introduction of acceptor engineering, the lysosome-targeting probe became more sensitive to β-gal in cells and tissues, boosting the discrimination of high β-gal-expressing ovarian cancer tumours from low β-gal-expressing tissues. Furthermore, the superiority of OELyso-Gal was validated in real-time visualization of ovarian cancer in tumour-bearing mice. This elegant acceptor engineering strategy provides inspirational insights into the development of customized fluorescent probes for monitoring disease-associated biomarkers within subcellular organelles.
    DOI:  https://doi.org/10.1039/d4sc00487f
  6. New Phytol. 2024 May 17.
    Exploring the connections between ER-based lipid metabolism and plasma membrane nanodomain signaling.
    Xue Pan, Sophia Mastrella, Mohinur Khamzaaliyeva, Didier-Deschamps Ashley.
      Recent advancements in our understanding of cell membrane dynamics have shed light on the importance of plasma membrane (PM) nanodomains in plant cell signaling. Nevertheless, many aspects of membrane nanodomains, including their regulatory mechanisms and biological functions, remain enigmatic. To address this knowledge gap, our review article proposes a novel perspective wherein signaling pathways target endoplasmic reticulum (ER)-based lipid metabolism to exert control over the formation and function of membrane nanodomains. Subsequently, these nanodomains reciprocate by influencing the localization and activity of signaling molecules at the PM. We place a specific emphasis on ER-based enzymatic reactions, given the ER's central role in membrane lipid biosynthesis and its capacity to directly impact PM lipid composition, particularly with regard to saturation levels - an essential determinant of nanodomain properties. The interplay among cell signaling, glycerolipid metabolism, and PM nanodomain may create feedforward/feedback loops that fine-tune cellular responses to developmental and environmental cues.
    Keywords:  ER‐based lipid metabolism; cell signaling; lipid remodeling; phospholipid composition; plasma membrane nanodomains; triacylglycerol synthesis
    DOI:  https://doi.org/10.1111/nph.19815
  7. Biomed Pharmacother. 2024 May 12. pii: S0753-3322(24)00591-2. [Epub ahead of print]175 116707
    Therapeutic antibody engineering for efficient targeted degradation of membrane proteins in lysosomes.
    Corentin Gauthier, Morgane Daurat, Lamiaa Mohamed Ahmed Ali, Khaled El Cheikh, Iris El Bahlagui, Camille Taliercio, Elodie Morère, Magali Gary-Bobo, Alain Morère, Marcel Garcia, Marie Maynadier, Ilaria Basile.
      Targeted degradation of pathological proteins is a promising approach to enhance the effectiveness of therapeutic monoclonal antibodies (mAbs) in cancer therapy. In this study, we demonstrate that this objective can be efficiently achieved by the grafting of mannose 6-phosphate analogues called AMFAs2 onto the therapeutic antibodies trastuzumab and cetuximab, both directed against membrane antigens. The grafting of AMFAs confers to these antibodies the novel property of being internalized via the mannose 6-phosphate receptor (M6PR) pathway. AMFA conjugation to these mAbs significantly increases their cellular uptake and leads to enhanced degradation of the target antigens in cancer cells. This results in a drastic inhibition of cancer cell proliferation compared to unconjugated mAbs, as demonstrated in various cancer cell lines, and an increased therapeutic efficacy in mouse and zebrafish xenografted models. These findings highlight the potential of this technology to improve therapeutic outcomes in cancer treatment.
    Keywords:  AMFA; Antibody engineering; Lysosome; Mannose 6-phosphate receptor; Mannose 6-phosphonate; Targeted protein degradation
    DOI:  https://doi.org/10.1016/j.biopha.2024.116707
  8. Clin Exp Reprod Med. 2024 May 17.
    The differential expression patterns of Atg9a and Atg9b in cells of the reproductive organs.
    Minseo Lee, Sujin Son, Hyunjung J Lim, Haengseok Song.
       Objective: Autophagy is a major intracellular catabolic pathway governed by the sequential actions of proteins encoded by autophagy-related genes (Atg). ATG9, the only transmembrane protein involved in this process, regulates phospholipid translocation to autophagosomes during the early phases of autophagy. In mammals, two Atg9 isoforms have been reported: Atg9a and Atg9b. In this study, we examined whether the molecular and cellular characteristics of these two isoforms differed in mice.
    Methods: Whole uteri were collected on days 1, 4, and 8 of pregnancy and from ovariectomized mice injected with vehicle, progesterone, or 17β-estradiol. Cells from reproductive tissues, such as granulosa cells, uterine epithelial cells (UECs), uterine stromal cells (USCs), and oocytes were collected. Two human uterine cell lines were also used in this analysis. Reverse transcription-polymerase chain reaction tests, Western blotting, and immunofluorescence staining were performed. Serum starvation conditions were used to induce autophagy in primary cells.
    Results: Atg9a and Atg9b were expressed in multiple mouse tissues and reproductive cells. Neither Atg9A nor Atg9B significantly changed in response to steroid hormones. Immunofluorescence staining of the UECs and USCs showed that ATG9A was distributed in a punctate-like pattern, whereas ATG9B exhibited a pattern of elongated tubular shapes in the cytoplasm. In human cancer cell lines, ATG9B was undetectable, whereas ATG9A was found in all cell types examined.
    Conclusion: The Atg9 isoforms exhibited distinct subcellular localizations in UECs and may play different roles in autophagy. Notably, human uterine cells exhibited reduced ATG9B expression, suggesting that this suppression may be due to epigenetic regulation.
    Keywords:  Atg9; Granulosa cells; Mice; Oocytes; Uterus
    DOI:  https://doi.org/10.5653/cerm.2023.06737
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