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
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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 (C 2 -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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Cytosolic cathepsins usually precipitate RCD by proteolytic activation or inactivation of substrates including BID, BAX, anti-apoptotic BCL2 family members, and XIAP, engaging feed-forward amplification involving MOMP and caspases.
“Cytosolic cathepsins usually precipitate RCD by catalyzing the proteolytic activation or inactivation of several substrates, including BID, BAX, anti-apoptotic BCL2 family members, and XIAP [776–778], hence engaging a feed-forward amplification circuitry of the lethal cascade involving MOMP and caspases.”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [778]
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- Authors
- Taniguchi, M., Ogiso, H., Takeuchi, T., Kitatani, K., Umehara, H., & Okazaki, T.
- Affiliations
- Kanazawa Medical University (JP)
- Tohoku University (JP)
- Kyoto University (JP)
- Corresponding author
- Okazaki, T
- Venue
- Cell Death & Disease
- Published
- 2015-04-09
- Volume
- 6
- Issue
- 4
- Pages
- e1717-e1717
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC4650549
- OpenAlex
- W1998308437
- Cited by
- 57
- References
- 68
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 3 · 2023: 6 · 2022: 10 · 2021: 6 · 2020: 5 · 2019: 3 · 2018: 6 · 2017: 6 · 2016: 4 · 2015: 1
- FWCI
- 2.46
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Death and Disease (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Takeda Science Foundation (S1201004)
- Mizutani Foundation for Glycoscience
- Ministry of Education, Culture, Sports, Science and Technology (H2012-16, S1201004)
- Kanazawa Medical University
- SENSHIN Medical Research Foundation
- Ono Pharmaceutical
- Japan Society for the Promotion of Science (2012-2015, 25870853, 21890144)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- acid sphingomyelinase, cathepsin B, caspase-dependent apoptosis, desipramine, lysosomal protein degradation
- MeSH terms
- Cathepsin B, Ceramides, Cytosol, Humans, Interleukin-2, Killer Cells, Natural, Lysosomes, Sphingomyelin Phosphodiesterase, Lymphoma, T-Cell, Apoptosis, Cell Line, Tumor, X-Linked Inhibitor of Apoptosis Protein, Caspase 3
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