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Valproic acid (VPA) has broad efficacy against several seizures but causes liver injury limiting its prolonged clinical use. Some studies have demonstrated that VPA-induced ...hepatotoxicity is characterized by microvesicular hepatic steatosis. However, novel detailed mechanisms to explain VPA-induced hepatic steatosis and experimentally rigorously validated protective agents are still lacking. In this study, 8-week-old C57BL/6J mice were gavaged with VPA (500 mg/kg/d) for 4 weeks to establish an in vivo model of VPA-induced chronic liver injury. Quantitative proteomic and non-targeted lipidomic analyses were performed to explore the underlying mechanisms of VPA-induced hepatotoxicity. As a result, VPA-induced hepatotoxicity is associated with impaired autophagic flux, which is attributed to lysosomal dysfunction. Further studies revealed that VPA-induced lysosomal membrane permeabilization (LMP), allows soluble lysosomal enzymes to leak into the cytosol, which subsequently led to impaired lysosomal acidification. A lower abundance of glycerophospholipids and an increased abundance of lysophospholipids in liver tissues of mice in the VPA group strongly indicated that VPA-induced LMP may be mediated by the activation of phospholipase PLA2G4A. Metformin (Met) acted as a potential protective agent attenuating VPA-induced liver dysfunction and excessive lipid accumulation. Molecular docking and cellular thermal shift assays demonstrated that Met inhibited the activity of PLA2G4A by directly binding to it, thereby ameliorating VPA-induced LMP and autophagic flux impairment. In conclusion, this study highlights the therapeutic potential of targeting PLA2G4A-mediated lysosomal dysfunction in VPA-induced hepatotoxicity.
In colorectal cancer patients, a high density of cytotoxic CD8+ T cells in tumors is associated with better prognosis. Using a Stat3 loss-of-function approach in two wnt/β-catenin-dependent ...autochthonous models of sporadic intestinal tumorigenesis, we unravel a complex intracellular process in intestinal epithelial cells (IECs) that controls the induction of a CD8+ T cell based adaptive immune response. Elevated mitophagy in IECs causes iron(II)-accumulation in epithelial lysosomes, in turn, triggering lysosomal membrane permeabilization. Subsequent release of proteases into the cytoplasm augments MHC class I presentation and activation of CD8+ T cells via cross-dressing of dendritic cells. Thus, our findings highlight a so-far-unrecognized link between mitochondrial function, lysosomal integrity, and MHC class I presentation in IECs and suggest that therapies triggering mitophagy or inducing LMP in IECs may prove successful in shifting the balance toward anti-tumor immunity in colorectal cancer.
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•Increased mitophagy in IECs triggers lysosomal membrane permeabilization•Lysosomal membrane permeabilization enhances antigen presentation in IECs•Enhanced antigen presentation in IECs augments MHC class I presentation•Mitophagy and lysosomal integrity in IECs regulate anti-tumor immunity
Enhanced mitophagy in intestinal epithelial cells promotes anti-tumor immunity through increasing lysosomal membrane permeabilization that augments MHC I presentation and CD8+ T cell activation.
Plant defensins were discovered at beginning of the 90s'; however, their precise mechanism of action is still unknown. Herein, we studied ApDef1-Saccharomyces cerevisiae interaction.
ApDef1-S. ...cerevisiae interaction was studied by determining the MIC, viability and death kinetic assays. Viability assay was repeated with hydroxyurea synchronized-yeast and pretreated with CCCP. Plasma membrane permeabilization, ROS induction, chromatin condensation, and caspase activation analyses were assessed through Sytox green, DAB, DAPI and FITC-VAD-FMK, respectively. Viability assay was done in presence of ascorbic acid and Z-VAD-FMK. Ultrastructural analysis was done by electron microscopy.
ApDef1 caused S. cerevisiae cell death and MIC was 7.8μM. Whole cell population died after 18h of ApDef1 interaction. After 3h, 98.76% of synchronized cell population died. Pretreatment with CCCP protected yeast from ApDef1 induced death. ApDef1-S. cerevisiae interaction resulted in membrane permeabilization, H2O2 increased production, chromatin condensation and caspase activation. Ascorbic acid prevented yeast cell death and membrane permeabilization. Z-VAD-FMK prevented yeast cell death.
ApDef1-S. cerevisiae interaction caused cell death through cell cycle dependentprocess which requires preserved membrane potential. After interaction, yeast went through uncontrolled ROS production and accumulation, which led to plasma membrane permeabilization, chromatin condensation and, ultimately, cell death by activation of caspase-dependent apoptosis via.
We show novel requirements for the interaction between plant defensin and fungi cells, i.e. cell cycle phase and membrane potential, and we indicate that membrane permeabilization is probably caused by ROS and therefore, it would be an indirect event of the ApDef1-S. cerevisiae interaction.
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•S. cerevisiae cell death induced by ApDef1 is a cell cycle-dependent process.•S. cerevisiae cell death induced by ApDef1 requires membrane potential.•ApDef1 caused uncontrolled ROS production and accumulation in S. cerevisiae.•Produced ROS by ApDef1 led to membrane permeabilization and chromatin condensation.•S. cerevisiae cell death induced by ApDef1 occurs via a caspase-dependent apoptosis process.
Lysosomes are membrane‐enclosed organelles that mediate the intracellular degradation of macromolecules. They play an essential role in calcium regulation and have emerged as key signaling hubs in ...controlling the nutrient response. Maintaining lysosomal integrity and function is therefore crucial for cellular homeostasis. Different forms of stress can induce lysosomal membrane permeabilization (LMP), resulting in the translocation to the cytoplasm of intralysosomal components, such as cathepsins, inducing lysosomal‐dependent cell death (LDCD). Here, we review recent advances that have furthered our understanding of the molecular mechanisms of LMP and the methods used to detect it. We discuss several endolysosomal damage‐response mechanisms that mediate the repair or elimination of compromised lysosomes and summarize the role of LMP and cathepsins in LDCD and other cell death pathways. Finally, with the emergence of lysosomes as promising therapeutic targets for several human diseases, we review a variety of therapeutic strategies that seek to either destabilize lysosomes or to maintain, enhance or restore lysosomal function.
Lysosomes mediate intracellular degradation through the action of lysosomal hydrolases. Lysosomal membrane permeabilization (LMP) results in translocation to the cytoplasm of the intraluminal contents and consequent lysosome‐dependent cell death.
Some forms of regulated cell death, such as apoptosis, are precipitated by the activation of cysteine proteases of the caspase family, including caspase 8, 9, and 3. Other caspases, such as caspase 1 ...and 4, are well known for their pro-inflammatory functions but regulate cell death in a limited number of pathophysiological settings. Accumulating evidence suggests that the most conserved function of mammalian caspases is not to control cell death sensu stricto, but to regulate inflammatory and immune reactions to dying cells and infectious challenges. Here, we review the molecular and cellular mechanisms though which mammalian caspases connect cell-death signaling to the maintenance of organismal homeostasis.
Accumulating evidence suggests that the main role of mammalian caspases is not to precipitate regulated cell death, but to control how the host perceives infected and dying cells. Kroemer and colleagues review these findings and provide insights into the mechanisms though which caspases connect cell-death signaling to the maintenance of organismal homeostasis.
Cells undergo diverse types of cell death. Many but not all types of programmed and regulated cell death (PCD and RCD) involve the permeabilization of the membrane through the formation of small ...pores (e.g., generated by gasdermins and MLKL (mixed lineage kinase domain-like protein).Plasma membrane rupture during necrotic cell death, long thought to be a passive process, is now understood to be orchestrated by the plasma membrane protein Ninjurin-1 (NINJ1).NINJ1 oligomerizes in the terminal stages of RCD, forming filamentous assemblies that can cap membrane edges and create lesions in the plasma membrane through which large damage-associated molecular patterns (DAMPs) are released.NINJ1 lesions are distinct from other types of plasma membrane permeabilization which are only large enough to exchange ions and small cytokines. NINJ1 lesions, on the other hand, can release large proteins or protein complexes including the DAMP HMGB1.It remains unclear what is the upstream signal common to RCD pathways that triggers NINJ1 lesions, and what role NINJ1 plays in human pathologies and mouse models.
Lytic cell death culminates in cell swelling and plasma membrane rupture (PMR). The cellular contents released, including proteins, metabolites, and nucleic acids, can act as danger signals and induce inflammation. During regulated cell death (RCD), lysis is actively initiated and can be preceded by an initial loss of membrane integrity caused by pore-forming proteins, allowing small molecules and cytokines to exit the cell. A recent seminal discovery showed that ninjurin1 (NINJ1) is the common executioner of PMR downstream of RCD, resulting in the release of large proinflammatory molecules and representing a novel target of cell death-associated lysis. We summarize recent developments in understanding membrane integrity and rupture of the plasma membrane with a focus on NINJ1.
Lytic cell death culminates in cell swelling and plasma membrane rupture (PMR). The cellular contents released, including proteins, metabolites, and nucleic acids, can act as danger signals and induce inflammation. During regulated cell death (RCD), lysis is actively initiated and can be preceded by an initial loss of membrane integrity caused by pore-forming proteins, allowing small molecules and cytokines to exit the cell. A recent seminal discovery showed that ninjurin1 (NINJ1) is the common executioner of PMR downstream of RCD, resulting in the release of large proinflammatory molecules and representing a novel target of cell death-associated lysis. We summarize recent developments in understanding membrane integrity and rupture of the plasma membrane with a focus on NINJ1.
Immunotherapy has received widespread attention for its effective and long‐term tumor‐eliminating ability. However, for immunogenic “cold” tumors, such as prostate cancer (PCa), the low ...immunogenicity of the tumor itself is a serious obstacle to efficacy. Here, this work reports a strategy to enhance PCa immunogenicity by triggering cascade self‐enhanced ferroptosis in tumor cells, turning the tumor from “cold” to “hot”. This work develops a transformable self‐assembled peptide TEP‐FFG‐CRApY with alkaline phosphatase (ALP) responsiveness and glutathione peroxidase 4 (GPX4) protein targeting. TEP‐FFG‐CRApY self‐assembles into nanoparticles under aqueous conditions and transforms into nanofibers in response to ALP during endosome/lysosome uptake into tumor cells, promoting lysosomal membrane permeabilization (LMP). On the one hand, the released TEP‐FFG‐CRAY nanofibers target GPX4 and selectively degrade the GPX4 protein under the light irradiation, inducing ferroptosis; on the other hand, the large amount of leaked Fe2+ further cascade to amplify the ferroptosis through the Fenton reaction. TEP‐FFG‐CRApY‐induced immunogenic ferroptosis improves tumor cell immunogenicity by promoting the maturation of dendritic cells (DCs) and increasing intratumor T‐cell infiltration. More importantly, recovered T cells further enhance ferroptosis by secreting large amounts of interferon‐gamma (IFN‐γ). This work provides a novel strategy for the molecular design of synergistic molecularly targeted therapy for immunogenic “cold” tumors.
This work develops a a smart supramolecular self‐assembled peptide TEP‐FFG‐CRApY for prostate cancer (PCa) immunotherapy. At tumor cells, TEP‐FFG‐CRApY initiates tumor cell cascade self‐enhanced immunogenic ferroptosis via enzyme‐triggered morphological transformation. The powerful immunomodulatory effect not only stimulates a solid antitumor immune response to suppress the primary tumor, but also creates a long‐term immune memory to prevent tumor metastasis.
•A signaling network linking apoptosis and inflammation by Bcl-2 family proteins is constructed.•The network is converted into an ODE model composed of four modules.•The simulation results are ...consistent with previous theoretical and experimental results.•The model makes several compelling predictions about cell fate regulation.
Recent studies delineate an intimate crosstalk between apoptosis and inflammation. However, the dynamic mechanism linking them by mitochondrial membrane permeabilization remains elusive. Here, we construct a mathematical model consisting of four functional modules. Bifurcation analysis reveals that bistability stems from Bcl-2 family member interaction and time series shows that the time difference between Cyt c and mtDNA release is around 30 min, which are consistent with previous works. The model predicts that Bax aggregation kinetic determines cells to undergo apoptosis or inflammation, and that modulating the inhibitory effect of caspase 3 on IFN-β production allows the concurrent occurrence of apoptosis and inflammation. This work provides a theoretical framework for exploring the mechanism of mitochondrial membrane permeabilization in controlling cell fate.
In 2009, the Nomenclature Committee on Cell Death (NCCD) proposed a set of recommendations for the definition of distinct cell death morphologies and for the appropriate use of cell death-related ...terminology, including 'apoptosis', 'necrosis' and 'mitotic catastrophe'. In view of the substantial progress in the biochemical and genetic exploration of cell death, time has come to switch from morphological to molecular definitions of cell death modalities. Here we propose a functional classification of cell death subroutines that applies to both in vitro and in vivo settings and includes extrinsic apoptosis, caspase-dependent or -independent intrinsic apoptosis, regulated necrosis, autophagic cell death and mitotic catastrophe. Moreover, we discuss the utility of expressions indicating additional cell death modalities. On the basis of the new, revised NCCD classification, cell death subroutines are defined by a series of precise, measurable biochemical features.
Cysteine cathepsin protease activity is frequently dysregulated in the context of neoplastic transformation. Increased activity and aberrant localization of proteases within the tumour ...microenvironment have a potent role in driving cancer progression, proliferation, invasion and metastasis. Recent studies have also uncovered functions for cathepsins in the suppression of the response to therapeutic intervention in various malignancies. However, cathepsins can be either tumour promoting or tumour suppressive depending on the context, which emphasizes the importance of rigorous in vivo analyses to ascertain function. Here, we review the basic research and clinical findings that underlie the roles of cathepsins in cancer, and provide a roadmap for the rational integration of cathepsin-targeting agents into clinical treatment.
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