bims-lymeca Biomed News
on Lysosome metabolism in cancer
Issue of 2022–06–05
eight papers selected by
Harilaos Filippakis, University of New England
  1. Non-canonical mTORC1 signaling at the lysosome.
  2. Branching Off: New Insight Into Lysosomes as Tubular Organelles.
  3. Therapeutic advantage of targeting lysosomal membrane integrity supported by lysophagy in malignant glioma.
  4. The fate of autophagosomal membrane components.
  5. The Achilles' heel of cancer: targeting tumors via lysosome-induced immunogenic cell death.
  6. ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA-dependent STING signaling.
  7. Artificial neural networks enable genome-scale simulations of intracellular signaling.
  8. Membrane contact sites and cytoskeleton-membrane interactions in autophagy.
  1. Trends Cell Biol. 2022 May 30. pii: S0962-8924(22)00117-9. [Epub ahead of print]
    Non-canonical mTORC1 signaling at the lysosome.
    Gennaro Napolitano, Chiara Di Malta, Andrea Ballabio.
      The mechanistic target of rapamycin complex 1 (mTORC1) signaling hub integrates multiple environmental cues to modulate cell growth and metabolism. Over the past decade considerable knowledge has been gained on the mechanisms modulating mTORC1 lysosomal recruitment and activation. However, whether and how mTORC1 is able to elicit selective responses to diverse signals has remained elusive until recently. We discuss emerging evidence for a 'non-canonical' mTORC1 signaling pathway that controls the function of microphthalmia/transcription factor E (MiT-TFE) transcription factors, key regulators of cell metabolism. This signaling pathway is mediated by a specific mechanism of substrate recruitment, and responds to stimuli that appear to converge on the lysosomal surface. We discuss the relevance of this pathway in physiological and disease conditions.
    Keywords:  FLCN; Rag GTPases; TFEB; lysosome; mTORC1
    DOI:  https://doi.org/10.1016/j.tcb.2022.04.012
  2. Front Cell Dev Biol. 2022 ;10 863922
    Branching Off: New Insight Into Lysosomes as Tubular Organelles.
    K Adam Bohnert, Alyssa E Johnson.
      Lysosomes are acidic, membrane-bound organelles that play essential roles in cellular quality control, metabolism, and signaling. The lysosomes of a cell are commonly depicted as vesicular organelles. Yet, lysosomes in fact show a high degree of ultrastructural heterogeneity. In some biological contexts, lysosome membranes naturally transform into tubular, non-vesicular morphologies. Though the purpose and regulation of tubular lysosomes has been historically understudied, emerging evidence suggests that tubular lysosomes may carry out unique activities, both degradative and non-degradative, that are critical to cell behavior, function, and viability. Here, we discuss recent advances in understanding the biological significance of tubular lysosomes in cellular physiology, and we highlight a growing number of examples that indicate the centrality of this special class of lysosomes to health and disease.
    Keywords:  aging; autophagy; cell biology; lysosome morphology; organelles; tubular lysosomes
    DOI:  https://doi.org/10.3389/fcell.2022.863922
  3. Cancer Sci. 2022 Jun 03.
    Therapeutic advantage of targeting lysosomal membrane integrity supported by lysophagy in malignant glioma.
    Yongwei Jing, Masahiko Kobayashi, Ha Thi Vu, Atsuko Kasahara, Xi Chen, Loc Thi Pham, Kenta Kurayoshi, Yuko Tadokoro, Masaya Ueno, Tomoki Todo, Mitsutoshi Nakada, Atsushi Hirao.
      Lysosomes function as the digestive system of a cell, which are involved in macromolecular recycling, vesicle trafficking, metabolic reprogramming, and pro-growth signaling. Although quality control of lysosome biogenesis is thought to be a potential target for cancer therapy, practical strategies have not been established. Here, we show that lysosomal membrane integrity supported by lysophagy, a selective autophagy for damaged lysosomes, is a promising therapeutic target for glioblastoma (GBM). In this study, we found that ifenprodil, an FDA-approved drug with neuromodulatory activities, efficiently inhibited spheroid formation of patient-derived GBM cells in a combination with autophagy inhibition. Ifenprodil increased intracellular Ca2+ level, resulting in mitochondrial reactive oxygen species-mediated cytotoxicity. The ifenprodil-induced Ca2+ elevation was due to Ca2+ release from lysosomes, but not endoplasmic reticulum, associated with galectin-3 punctation as an indicator of lysosomal membrane damage. Since the Ca2+ release was enhanced by ATG5 deficiency, autophagy protected against lysosomal membrane damage. By comparative analysis of 765 FDA-approved compounds, we identified another clinically available drug for CNS diseases, amoxapine, in addition to ifenprodil. Both compounds promoted degradation of lysosomal membrane proteins, indicating a critical role of lysophagy in quality control of lysosomal membrane integrity. Importantly, a synergistic inhibitory effect of ifenprodil and chloroquine, a clinically available autophagy inhibitor, on spheroid formation was remarkable in GBM cells, but not in non-transformed neural progenitor cells. Finally, chloroquine dramatically enhanced effects of the compounds inducing lysosomal membrane damage in a patient-derived xenograft model. These data demonstrate a therapeutic advantage of targeting lysosomal membrane integrity in GBM.
    Keywords:  Lysosomal membrane turnover; autophagy; calcium; glioblastoma; lysosomal membrane integrity
    DOI:  https://doi.org/10.1111/cas.15451
  4. Autophagy. 2022 Jun 02. 1-2
    The fate of autophagosomal membrane components.
    Zhe Wu, Chuchu Zhou, Huilin Que, Yufen Wang, Yueguang Rong.
      During macroautophagy/autophagy, autophagosomes fuse with lysosomes to form autolysosomes. After fusion, the autophagosome inner membrane and enclosed substrates are degraded and transported out of lysosomes for recycling. The lysosomal membrane components are recycled by autophagic lysosome reformation (ALR) to generate new lysosomes. However, the fate of autophagosome outer membrane components on autolysosomes remains unknown. Our recent work discovered that autophagosome outer membrane components are not degraded but are recycled through an unidentified process which we named autophagosomal components recycling (ACR). Further investigation revealed the recycler complex (SNX4-SNX5-SNX17) responsible for ACR. The discovery of ACR not only fills a missing part in autophagy, but also reveals a new recycling pathway on autolysosomes.
    Keywords:  ATG9A; STX17; autophagosomal components recycling; autophagy; lysosome
    DOI:  https://doi.org/10.1080/15548627.2022.2083807
  5. Cell Death Dis. 2022 May 30. 13(5): 509
    The Achilles' heel of cancer: targeting tumors via lysosome-induced immunogenic cell death.
    Taritsa Iulianna, Neote Kuldeep, Fossel Eric.
      Interest in the lysosome's potential role in anticancer therapies has recently been appreciated in the field of immuno-oncology. Targeting lysosomes triggers apoptotic pathways, inhibits cytoprotective autophagy, and activates a unique form of apoptosis known as immunogenic cell death (ICD). This mechanism stimulates a local and systemic immune response against dead-cell antigens. Stressors that can lead to ICD include an abundance of ROS which induce lysosome membrane permeability (LMP). Dying cells express markers that activate immune cells. Dendritic cells engulf the dying cell and then present the cell's neoantigens to T cells. The discovery of ICD-inducing agents is important due to their potential to trigger autoimmunity. In this review, we discuss the various mechanisms of activating lysosome-induced cell death in cancer cells specifically and the strategies that current laboratories are using to selectively promote LMP in tumors.
    DOI:  https://doi.org/10.1038/s41419-022-04912-8
  6. J Cell Biol. 2022 Jul 04. pii: e202106046. [Epub ahead of print]221(7):
    ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA-dependent STING signaling.
    William Hancock-Cerutti, Zheng Wu, Peng Xu, Narayana Yadavalli, Marianna Leonzino, Arun Kumar Tharkeshwar, Shawn M Ferguson, Gerald S Shadel, Pietro De Camilli.
      Mutations in VPS13C cause early-onset, autosomal recessive Parkinson's disease (PD). We have established that VPS13C encodes a lipid transfer protein localized to contact sites between the ER and late endosomes/lysosomes. In the current study, we demonstrate that depleting VPS13C in HeLa cells causes an accumulation of lysosomes with an altered lipid profile, including an accumulation of di-22:6-BMP, a biomarker of the PD-associated leucine-rich repeat kinase 2 (LRRK2) G2019S mutation. In addition, the DNA-sensing cGAS-STING pathway, which was recently implicated in PD pathogenesis, is activated in these cells. This activation results from a combination of elevated mitochondrial DNA in the cytosol and a defect in the degradation of activated STING, a lysosome-dependent process. These results suggest a link between ER-lysosome lipid transfer and innate immune activation in a model human cell line and place VPS13C in pathways relevant to PD pathogenesis.
    DOI:  https://doi.org/10.1083/jcb.202106046
  7. Nat Commun. 2022 Jun 02. 13(1): 3069
    Artificial neural networks enable genome-scale simulations of intracellular signaling.
    Avlant Nilsson, Joshua M Peters, Nikolaos Meimetis, Bryan Bryson, Douglas A Lauffenburger.
      Mammalian cells adapt their functional state in response to external signals in form of ligands that bind receptors on the cell-surface. Mechanistically, this involves signal-processing through a complex network of molecular interactions that govern transcription factor activity patterns. Computer simulations of the information flow through this network could help predict cellular responses in health and disease. Here we develop a recurrent neural network framework constrained by prior knowledge of the signaling network with ligand-concentrations as input and transcription factor-activity as output. Applied to synthetic data, it predicts unseen test-data (Pearson correlation r = 0.98) and the effects of gene knockouts (r = 0.8). We stimulate macrophages with 59 different ligands, with and without the addition of lipopolysaccharide, and collect transcriptomics data. The framework predicts this data under cross-validation (r = 0.8) and knockout simulations suggest a role for RIPK1 in modulating the lipopolysaccharide response. This work demonstrates the feasibility of genome-scale simulations of intracellular signaling.
    DOI:  https://doi.org/10.1038/s41467-022-30684-y
  8. FEBS Lett. 2022 Jun 01.
    Membrane contact sites and cytoskeleton-membrane interactions in autophagy.
    Patrick J Duckney, Pengwei Wang, Patrick J Hussey.
      In Eukaryotes, organelle interactions occur at specialised contact sites between organelle membranes. Contact sites are regulated by specialised tethering proteins, which bring organelle membranes into close proximity, and facilitate functional crosstalk between compartments. Whilst contact site proteins are well characterised in mammals and yeast, the regulators of plant contact site formation are only now beginning to emerge. Having unique subcellular structures, plants must also utilise unique mechanisms of organelle interaction to regulate plant-specific functions. The recently characterised NETWORKED proteins are the first dedicated family of plant-specific contact site proteins. Research into the NET proteins and their interacting partners continues to uncover plant-specific mechanisms of organelle interaction and the importance of these organelle contacts to plant life. Moreover, it is becoming increasingly apparent that organelle interactions are fundamental to autophagy in plants. Here, we will present recent developments in our understanding of the mechanisms of plant organelle interactions, their functions, and emerging roles in autophagy.
    Keywords:  Actin; Autophagy; Chloroplast; Contact Site; Cytoskeleton; Endoplasmic Reticulum; Membrane; Mitochondria; Plasma Membrane; Vacuole
    DOI:  https://doi.org/10.1002/1873-3468.14414
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