bims-lycede Biomed News
on Lysosome-dependent cell death
Issue of 2024–12–22
six papers selected by
Sofía Peralta, Universidad Nacional de Cuyo
  1. The cGAS-STING pathway activates transcription factor TFEB to stimulate lysosome biogenesis and pathogen clearance.
  2. Development and Application of a BODIPY Carbazole Derivative Probe for Lysosomal Imaging: Insights into Lysosomal Dynamics and Dysfunction in Inflammation-Related Diseases.
  3. BODIPYS Based Fluorescent Markers To Monitor Autophagic Lysosomes and Lipid Droplets in TNBC.
  4. Unveiling the Role of Mechanistic Target of Rapamycin Kinase (MTOR) Signaling in Cancer Progression and the Emergence of MTOR Inhibitors as Therapeutic Strategies.
  5. Multi-Omics Profiling and Experimental Verification of Lysosomes-Related Genes in Hepatocellular Carcinoma.
  6. Dysregulation of PI4P in the trans Golgi regions activates the mammalian Golgi stress response.
  1. Immunity. 2024 Dec 12. pii: S1074-7613(24)00532-6. [Epub ahead of print]
    The cGAS-STING pathway activates transcription factor TFEB to stimulate lysosome biogenesis and pathogen clearance.
    Yinfeng Xu, Qian Wang, Jun Wang, Chuying Qian, Yusha Wang, Sheng Lu, Lijiang Song, Zhengfu He, Wei Liu, Wei Wan.
      Induction of autophagy is an ancient function of the cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway through which autophagic cargoes are delivered to lysosomes for degradation. However, whether lysosome function is also modulated by the cGAS-STING pathway remains unknown. Here, we discovered that the cGAS-STING pathway upregulated lysosomal activity by stimulating lysosome biogenesis independently of the downstream protein kinase TANK-binding kinase 1 (TBK1). STING activation enhanced lysosome biogenesis through inducing the nuclear translocation of transcription factor EB (TFEB) as well as its paralogs transcription factor E3 (TFE3) and microphthalmia-associated transcription factor (MITF). STING-induced lipidation of GABA type A receptor-associated protein (GABARAP), an autophagy-related protein, on STING vesicles was responsible for TFEB activation. Membrane-bound GABARAP sequestered the GTPase-activating protein folliculin (FLCN) and FLCN-interacting protein (FNIP) complex to block its function toward the Rag GTPases Ras-related GTP-binding C and D (RagC and RagD), abolishing mechanistic target of rapamycin (mTOR) complex 1 (mTORC1)-dependent phosphorylation and inactivation of TFEB. Functionally, STING-induced lysosome biogenesis within cells facilitated the clearance of cytoplasmic DNA and invading pathogens. Thus, our findings reveal that induction of lysosome biogenesis is another important function of the cGAS-STING pathway.
    Keywords:  STING; TFEB; cGAS; innate immunity; lysosome
    DOI:  https://doi.org/10.1016/j.immuni.2024.11.017
  2. ACS Appl Mater Interfaces. 2024 Dec 17.
    Development and Application of a BODIPY Carbazole Derivative Probe for Lysosomal Imaging: Insights into Lysosomal Dynamics and Dysfunction in Inflammation-Related Diseases.
    Liping Su, Panyi Hu, Xinmei Luo, Haitao Ding, Rundong Zhang, Yeben Qian, Shiqian Qi, Xiaohe Tian, Wenwu Ling.
      Inflammation is crucial in neurodegenerative and chronic diseases, including Alzheimer disease (AD) and liver fibrosis. To gain a deeper understanding of lysosomal functions in cellular physiology and disease mechanisms, we developed a carbazole-based BODIPY lysosomal probe, designated LysoI. This probe specifically targets lysosomes within 15 min and exhibits a Stokes shift of approximately 180 nm, enabling continuous incubation for up to 5 h without the need for washing steps. Interestingly, LysoI remained effective for long-term imaging, even up to 24 h poststaining. Despite varying pH values and conditions, such as autophagy, apoptosis, and inflammation, it consistently provides excellent lysosomal imaging. Notably, inflammation disrupts lysosomal morphology and motility, as evidenced by an increased size, a decrease in number, and a reduction in movement speed, as observed with LysoI. Furthermore, lysosomal rupture and impaired clearance may exacerbate inflammation and contribute to cellular apoptosis. These findings suggest that lysosomal dysfunction is closely associated with disease progression; therefore, protection and repair targeting lysosomes may offer promising strategies for treating inflammation-related diseases.
    Keywords:  fluorescent probe; inflammation; liver fibrosis; lysosomes; neurodegenerative diseases
    DOI:  https://doi.org/10.1021/acsami.4c17607
  3. ACS Med Chem Lett. 2024 Dec 12. 15(12): 2115-2120
    BODIPYS Based Fluorescent Markers To Monitor Autophagic Lysosomes and Lipid Droplets in TNBC.
    Jaydeepsinh Chavda, Arjun Siwach, Sudhir Sabharwal, Anu Janaagal, Dhiraj Bhatia, Iti Gupta.
      Lysosomal enzymes and high accumulation of lipid droplets are associated with breast cancer. The lysosomes and lipid droplets were monitored by BODIPYs, acting as autophagy activators in cancer cells. BD-1 and BD-2 were synthesized and characterized by Mass, UV-visible, fluorescence, and NMR spectroscopies. In BODIPYs, the effect of carbazole groups was reflected by the large Stokes shifts (2143-1651 cm-1) and red fluorescence. BODIPYs generated ROS and induced autophagy in triple negative breast cancer cells (MDA-MB-231) under white light. Confocal experiments revealed that BD-1 and BD-2 preferentially colocalized in lysosomes and lipid droplets. Autophagic lysosomes and lipid droplets released Ca2+ ions in the cytoplasm, which was evident with blue fluorescence of Fura-2M dye. In combination with an autophagy inhibitor, BD-1 displayed excellent photocytotoxicity (5.57 μM) on triple negative breast cancer cells under white light. This work demonstrates the potential of BODIPYs as theranostic agents for the photodynamic therapy against TNBC.
    DOI:  https://doi.org/10.1021/acsmedchemlett.4c00275
  4. ACS Pharmacol Transl Sci. 2024 Dec 13. 7(12): 3758-3779
    Unveiling the Role of Mechanistic Target of Rapamycin Kinase (MTOR) Signaling in Cancer Progression and the Emergence of MTOR Inhibitors as Therapeutic Strategies.
    Devashish Mehta, Kajal Rajput, Dolly Jain, Avinash Bajaj, Ujjaini Dasgupta.
      The mechanistic target of rapamycin kinase (MTOR) is pivotal for cell growth, metabolism, and survival. It functions through two distinct complexes, mechanistic TORC1 and mechanistic TORC2 (mTORC1 and mTORC2). These complexes function in the development and progression of cancer by regulating different cellular processes, such as protein synthesis, lipid metabolism, and glucose homeostasis. The mTORC1 complex senses nutrients and initiates proliferative signals, and mTORC2 is crucial for cell survival and cytoskeletal rearrangements. mTORC1 and mTORC2 have therefore emerged as potential targets for cancer treatment. Several mTOR inhibitors, including rapamycin and its analogs (rapalogs), primarily target mTORC1 and are effective for specific cancer types. However, these inhibitors often lead to resistance and limited long-term advantages due to the activation of survival pathways through feedback mechanisms. Researchers have created next-generation inhibitors targeting mTORC1 and mTORC2 and dual PI3K/mTOR inhibitors to address these difficulties. These inhibitors demonstrate enhanced anti-tumor effects by simultaneously disrupting multiple signaling pathways and show promise for improved and long-lasting therapies. However, development of resistance and adverse side effects remain a significant obstacle. Recent additions known as RapaLinks have emerged as a boon to counter drug-resistant cancer cells, as they are more potent and provide a more comprehensive blockade of mTOR signaling pathways. This Review combines current research findings and clinical insights to enhance our understanding of the crucial role of mTOR signaling in cancer biology and highlights the evolution of mTOR inhibitors as promising therapeutic approaches.
    DOI:  https://doi.org/10.1021/acsptsci.4c00530
  5. J Cell Mol Med. 2024 Dec;28(24): e70225
    Multi-Omics Profiling and Experimental Verification of Lysosomes-Related Genes in Hepatocellular Carcinoma.
    Zhiyong Wang, Guoliang Wang, Peng Zhao, Ping Sun.
      Lysosomes play a crucial role in regulating the growth, invasion and metastasis of different tumour types. However, the specific function of lysosomes in hepatocellular carcinoma (HCC) remains uncertain. We retrieved gene expression and clinical data from the TCGA and GEO databases for HCC samples and established a new lysosome-associated prognostic therapeutic index (LAPTI) based on lysosome-related genes through machine learning. We then systematically analysed clinical characteristics, functional enrichment, tumour immune microenvironment, molecular docking, chemotherapy response and immunotherapy response in HCC. LAPTI, composed of four lysosome-related genes (CTSV, LAPTM4B, DNAJC6, AP1M2), is a reliable prognostic indicator for hepatocellular carcinoma patients and is validated in external data sets. Compared with the low LAPTI group, the high LAPTI group showed poorer prognosis and higher immune cell infiltration levels. We also observed that knocking down CTSV in vitro inhibited the proliferation and migration of hepatocellular carcinoma. This study provides valuable insights into the future clinical treatment of hepatocellular carcinoma by accurately assessing the prognosis of patients with hepatocellular carcinoma.
    Keywords:  CTSV; hepatocellular carcinoma; immunotherapy efficacy; lysosomes; molecular docking; prognosis
    DOI:  https://doi.org/10.1111/jcmm.70225
  6. J Biol Chem. 2024 Dec 13. pii: S0021-9258(24)02577-8. [Epub ahead of print] 108075
    Dysregulation of PI4P in the trans Golgi regions activates the mammalian Golgi stress response.
    Kanae Sasaki, Marika Toide, Takuya Adachi, Fumi Morishita, Yuto Watanabe, Hajime Tajima Sakurai, Sadao Wakabayashi, Satoshi Kusumi, Toshiyuki Yamaji, Kaori Sakurai, Daisuke Koga, Kentaro Hanada, Masafumi Yohda, Hiderou Yoshida.
      The Golgi stress response is an important cytoprotective system that enhances Golgi function in response to cellular demand, while cells damaged by prolonged Golgi stress undergo cell death. OSW-1, a natural compound with anticancer activity, potently inhibits OSBP that transports cholesterol and phosphatidylinositol-4-phosphate (PI4P) at contact sites between the endoplasmic reticulum and the Golgi apparatus. Previously, we reported that OSW-1 induces the Golgi stress response, resulting in Golgi stress-induced transcription and cell death. However, the underlying molecular mechanism has been unknown. To reveal the mechanism of a novel pathway of the Golgi stress response regulating transcriptional induction and cell death (the PI4P pathway), we performed a genome-wide knockout screen and found that transcriptional induction as well as cell death induced by OSW-1 was repressed by the loss of regulators of PI4P synthesis, such as PITPNB and PI4KB. Our data indicate that OSW-1 induces Golgi stress-dependent transcriptional induction and cell death through dysregulation of the PI4P metabolism in the Golgi.
    Keywords:  Golgi stress response; OSW-1; cancer; phosphatidylinositol-4-phosphate; the Genome-wide CRISPR-Cas9 knockout screening
    DOI:  https://doi.org/10.1016/j.jbc.2024.108075
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