XIAP discriminates between type I and type II FAS-induced apoptosis
Open accessAbstract
FAS (also called APO-1 and CD95) and its physiological ligand, FASL, regulate apoptosis of unwanted or dangerous cells, functioning as a guardian against autoimmunity and cancer development. Distinct cell types differ in the mechanisms by which the 'death receptor' FAS triggers their apoptosis. In type I cells, such as lymphocytes, activation of 'effector caspases' by FAS-induced activation of caspase-8 suffices for cell killing, whereas in type II cells, including hepatocytes and pancreatic beta-cells, caspase cascade amplification through caspase-8-mediated activation of the pro-apoptotic BCL-2 family member BID (BH3 interacting domain death agonist) is essential. Here we show that loss of XIAP (X-chromosome linked inhibitor of apoptosis protein) function by gene targeting or treatment with a second mitochondria-derived activator of caspases (SMAC, also called DIABLO; direct IAP-binding protein with low pI) mimetic drug in mice rendered hepatocytes and beta-cells independent of BID for FAS-induced apoptosis. These results show that XIAP is the critical discriminator between type I and type II apoptosis signalling and suggest that IAP inhibitors should be used with caution in cancer patients with underlying liver conditions.
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In type II cells (e.g., hepatocytes, pancreatic β cells, and a majority of cancer cells), CASP3 and CASP7 activation is restrained by XIAP.
“Conversely, in “type II cells” (e.g., hepatocytes, pancreatic β cells, and a majority of cancer cells), in which CASP3 and CASP7 activation is restrained by XIAP [310]”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [310]
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- Authors
- Jost, P. J., Grabow, S., Gray, D., McKenzie, M. D., Nachbur, U., Huang, D. C. S., Bouillet, P., Thomas, H. E., Borner, C., Silke, J., Strasser, A., & Kaufmann, T.
- Affiliations
- The University of Melbourne (AU)
- Walter and Eliza Hall Institute of Medical Research (AU)
- La Trobe University (AU)
- St Vincents Institute of Medical Research (AU)
- University of Freiburg (DE)
- University of Bern (CH)
- Corresponding author
- Strasser, Andreas
- Kaufmann, Thomas
- ORCID
- Venue
- Nature
- Published
- 2009-07-22
- Volume
- 460
- Issue
- 7258
- Pages
- 1035-1039
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2956120
- OpenAlex
- W1998198750
- Cited by
- 482
- References
- 36
- Citations by year
- 2026: 10 · 2025: 17 · 2024: 13 · 2023: 24 · 2022: 28 · 2021: 23 · 2020: 30 · 2019: 22 · 2018: 27 · 2017: 39 · 2016: 32 · 2015: 22 · 2014: 39 · 2013: 44 · 2012: 37
- FWCI
- 15.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- BORIS (University Library Bern) (submittedVersion)
- Funders
- National Cancer Institute (#CA 80188, R01CA043540, CA 43540, R01CA080188)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- XIAP, Fas, Fas ligand, apoptosis, caspase-8, caspase-9, Bid, Smac/DIABLO, IAP inhibitors, hepatocytes, pancreatic beta cells, lymphocytes, cancer therapy, liver disease, autoimmunity, carcinogenesis, cell death signaling, gene targeting, IAP antagonists
- MeSH terms
- Animals, Enzyme Activation, Female, Hepatitis, Male, Mice, Inbred C57BL, Thymus Gland, Signal Transduction, Apoptosis, fas Receptor, Hepatocytes, Biomimetic Materials, BH3 Interacting Domain Death Agonist Protein, Mice, X-Linked Inhibitor of Apoptosis Protein, Fas Ligand Protein, Caspase Inhibitors
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