ArticleCell death & disease2015
Lysosomal ceramide generated by acid sphingomyelinase triggers cytosolic cathepsin B-mediated degradation of X-linked inhibitor of apoptosis protein in natural killer/T lymphoma cell apoptosis.
Article in Cell death & disease, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 57 citations in OpenAlex.
- Article
- SMPD1 as a Potential Prognostic Biomarker in Glioma Is Associated With an Immunosuppressive Microenvironment.CNS neuroscience & therapeutics · 2026Article
- LIPL-1 and LIPL-2 are TCER-1-regulated lysosomal lipases with distinct roles in immunity and fertility.PLoS genetics · 2025Article
- Ceramide signaling in immunity: a molecular perspective.Lipids in health and disease · 2025Review
- Podocyte-specific silencing of acid sphingomyelinase gene to abrogate hyperhomocysteinemia-induced NLRP3 inflammasome activation and glomerular inflammation.American journal of physiology. Renal physiology · 2024Article
- Initiation of acute pancreatitis in mice is independent of fusion between lysosomes and zymogen granules.Cellular and molecular life sciences : CMLS · 2024Article
- Sphingolipid-Induced Bone Regulation and Its Emerging Role in Dysfunction Due to Disease and Infection.International journal of molecular sciences · 2024Review
- Acid Ceramidase Inhibitor LCL-805 Antagonizes Akt Signaling and Promotes Iron-Dependent Cell Death in Acute Myeloid Leukemia.Cancers · 2023Article
- Polyphyllin D punctures hypertrophic lysosomes to reverse drug resistance of hepatocellular carcinoma by targeting acid sphingomyelinase.Molecular therapy : the journal of the American Society of Gene Therapy · 2023Article
- Oxidative stress induces lysosomal membrane permeabilization and ceramide accumulation in retinal pigment epithelial cells.Disease models & mechanisms · 2023Article
- TFEB-mediated lysosomal exocytosis alleviates high-fat diet-induced lipotoxicity in the kidney.JCI insight · 2023Article
- The old second messenger cAMP teams up with novel cell death mechanisms: potential translational therapeutical benefit for Alzheimer's disease and Parkinson's disease.Frontiers in physiology · 2023Review
- Advancements on the Multifaceted Roles of Sphingolipids in Hematological Malignancies.International journal of molecular sciences · 2022Review
- Sphingosine-1-Phosphate Alleviates Irradiation Induced Salivary Gland Hypofunction through Preserving Endothelial Cells and Resident Macrophages.Antioxidants (Basel, Switzerland) · 2022Article
- Ceramide Metabolism Regulated by Sphingomyelin Synthase 2 Is Associated with Acquisition of Chemoresistance via Exosomes in Human Leukemia Cells.International journal of molecular sciences · 2022Article
- Lysosomal ceramides regulate cathepsin B-mediated processing of saposin C and glucocerebrosidase activity.Human molecular genetics · 2022Article
- Crosstalk between dihydroceramides produced by Porphyromonas gingivalis and host lysosomal cathepsin B in the promotion of osteoclastogenesis.Journal of cellular and molecular medicine · 2022Article
- Sphingolipids and Lymphomas: A Double-Edged Sword.Cancers · 2022Review
- Acid Sphingomyelinase Deficiency: A Clinical and Immunological Perspective.International journal of molecular sciences · 2021Review
- A novel mechanism of thrombocytopenia by PS exposure through TMEM16F in sphingomyelin synthase 1 deficiency.Blood advances · 2021Article
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
We previously reported that IL-2 deprivation induced acid sphingomyelinase-mediated (ASM-mediated) ceramide elevation and apoptosis in an NK/T lymphoma cell line KHYG-1. However, the molecular mechanism of ASM-ceramide-mediated apoptosis during IL-2 deprivation is poorly understood. Here, we showed that IL-2 deprivation induces caspase-dependent apoptosis characterized by phosphatidylserine externalization, caspase-8, -9, and -3 cleavage, and degradation of X-linked inhibitor of apoptosis protein (XIAP). IL-2 re-supplementation rescued apoptosis via inhibition of XIAP degradation without affecting caspase cleavage. However, IL-2 deprivation induced ceramide elevation via ASM in lysosomes and activated lysosomal cathepsin B (CTSB) but not cathepsin D. A CTSB inhibitor CA-074 Me and knockdown of CTSB inhibited ceramide-mediated XIAP degradation and apoptosis. Inhibition of ceramide accumulation in lysosomes using an ASM inhibitor, desipramine, decreased cytosolic activation of CTSB by inhibiting its transfer into cytosol from the lysosome. Knockdown of ASM also inhibited XIAP degradation and apoptosis. Furthermore, cell permeable N-acetyl sphingosine (C2-ceramide), which increases mainly endogenous d18:1/16:0 and d18:1/24:1 ceramide-like IL-2 deprivation, induced caspase-dependent apoptosis with XIAP degradation through CTSB. These findings suggest that lysosomal ceramide produced by ASM mediates XIAP degradation by activation of cytosolic CTSB and caspase-dependent apoptosis. The ASM-ceramide-CTSB signaling axis is a novel pathway of ceramide-mediated apoptosis in IL-2-deprived NK/T lymphoma cells.
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