ArticleCell cycle (Georgetown, Tex.)2015
Distinct cathepsins control necrotic cell death mediated by pyroptosis inducers and lysosome-destabilizing agents.
Article in Cell cycle (Georgetown, Tex.), 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 47 citations in OpenAlex.
- 6-Shogaol attenuates cisplatin-induced gastrointestinal inflammation involving modulation of the putative mTOR/TFEB-mediated autophagy-lysosomal pathway.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Targeting lysosome-dependent cell death in cancer: towards therapeutic strategies.Biomarker research · 2026Review
- Targeting Glycolysis with 2-Deoxy-D-Glucose and Lysosomal Integrity with L-Leucyl-L-Leucine Methyl Ester as Antimelanoma Strategy.Pharmaceutics · 2025Article
- Programmed cell revival from imminent cell death enhances tissue repair and regeneration.The EMBO journal · 2025Article
- Article
- Coronavirus Lung Infection Impairs Host Immunity against Secondary Bacterial Infection by Promoting Lysosomal Dysfunction.Journal of immunology (Baltimore, Md. : 1950) · 2022Article
- Probiotics: Evolving as a Potential Therapeutic Option against Acetaminophen-Induced Hepatotoxicity.Biomedicines · 2022Review
- Low-level lysosomal membrane permeabilization for limited release and sublethal functions of cathepsin proteases in the cytosol and nucleus.FEBS open bio · 2022Review
- Role of NLRP3 Inflammasome in Myocardial Ischemia-Reperfusion Injury and Ventricular Remodeling.Medical science monitor : international medical journal of experimental and clinical research · 2022Review
- Spatial localization of cathepsins: Implications in immune activation and resolution during infections.Frontiers in immunology · 2022Review
- Death Pathways of Cancer Cells Modulated by Surface Molecule Density on Gold Nanorods.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2021Article
- Article
- Lysosomal disruption by orthopedic wear particles induces activation of the NLRP3 inflammasome and macrophage cell death by distinct mechanisms.Journal of orthopaedic research : official publication of the Orthopaedic Research Society · 2021Article
- Article
- The role of cysteine peptidases in coronavirus cell entry and replication: The therapeutic potential of cathepsin inhibitors.PLoS pathogens · 2020Review
- The role of lysosome in regulated necrosis.Acta pharmaceutica Sinica. B · 2020Review
- Cathepsin A knockdown decreases the proliferation and invasion of A549 lung adenocarcinoma cells.Molecular medicine reports · 2020Article
- Verteporfin-induced lysosomal compartment dysregulation potentiates the effect of sorafenib in hepatocellular carcinoma.Cell death & disease · 2019Article
- The Pyroptotic Cell Death Effector Gasdermin D Is Activated by Gout-Associated Uric Acid Crystals but Is Dispensable for Cell Death and IL-1β Release.Journal of immunology (Baltimore, Md. : 1950) · 2019Article
- Lipid-induced lysosomal damage after demyelination corrupts microglia protective function in lysosomal storage disorders.The EMBO journal · 2019Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 3 countries.
Funding
Abstract
Necrotic cell death triggers a range of biological responses including a strong adaptive immune response, yet we know little about the cellular pathways that control necrotic cell death. Inhibitor studies suggest that proteases, and in particular cathepsins, drive necrotic cell death. The cathepsin B-selective inhibitor CA-074-Me blocks all forms of programmed necrosis by an unknown mechanism. We found that cathepsin B deficiency does not prevent induction of pyroptosis and lysosome-mediated necrosis suggesting that CA-074-Me blocks necrotic cell death by targeting cathepsins other than cathepsin B. A single cathepsin, cathepsin C, drives necrotic cell death mediated by the lysosome-destabilizing agent Leu-Leu-OMe (LLOMe). Here we present evidence that cathepsin C-deficiency and CA-074-Me block LLOMe killing in a distinct and cell type-specific fashion. Cathepsin C-deficiency and CA-074-Me block LLOMe killing of all myeloid cells, except for neutrophils. Cathepsin C-deficiency, but not CA-074-Me, blocks LLOMe killing of neutrophils suggesting that CA-074-Me does not target cathepsin C directly, consistent with inhibitor studies using recombinant cathepsin C. Unlike other cathepsins, cathepsin C lacks endoproteolytic activity, and requires activation by other lysosomal proteases, such as cathepsin D. Consistent with this theory, we found that lysosomotropic agents and cathepsin D downregulation by siRNA block LLOMe-mediated necrosis. Our findings indicate that a proteolytic cascade, involving cathepsins C and D, controls LLOMe-mediated necrosis. In contrast, cathepsins C and D were not required for pyroptotic cell death suggesting that distinct cathepsins control pyroptosis and lysosome-mediated necrosis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.