Cited by 57Sphingolipid Metabolism and SignalingCell death mechanisms and regulationLysosomal Storage Disorders Research

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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Taniguchi, M, Ogiso, H, Takeuchi, T, Kitatani, K, Umehara, H, Okazaki, T·2015·Cell Death & Disease

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 (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.”

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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)
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
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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