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XIAP discriminates between type I and type II FAS-induced apoptosis

Nature volume 460, pages 1035–1039 (2009)Cite this article

Abstract

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 development1,2,3,4. Distinct cell types differ in the mechanisms by which the ‘death receptor’ FAS triggers their apoptosis1,2,3,4. 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 β-cells, caspase cascade amplification through caspase-8-mediated activation of the pro-apoptotic BCL-2 family member BID (BH3 interacting domain death agonist)5 is essential6,7,8. Here we show that loss of XIAP (X-chromosome linked inhibitor of apoptosis protein)9,10 function by gene targeting or treatment with a second mitochondria-derived activator of caspases (SMAC11, also called DIABLO12; direct IAP-binding protein with low pI) mimetic drug in mice rendered hepatocytes and β-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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Figure 1: Levels of XIAP, caspase activation and proteolysis of caspase substrates in FASL-treated thymocytes and hepatocytes.
Figure 2: Loss of XIAP re-sensitises Bid -/- mice to FASL-induced fatal hepatitis.
Figure 3: Caspase inhibitors protect Bid -/- Xiap -/- hepatocytes from FASL-induced apoptosis.
Figure 4: The SMAC-mimetic drug BV6 sensitises BID-deficient mice to FASL-induced hepatocyte destruction.

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Acknowledgements

We thank D. Vaux, J. Tschopp, S. Cory, J. Adams, S. Nagata and Y. Lazebnik for gifts of mice and reagents, K. Vella, D. Cooper and G. Siciliano for animal care, B. Helbert for genotyping, the Biochemistry Department of the Royal Melbourne Hospital for ALT/AST measurements, C. Young and D. Chau for technical assistance and D. Vaux, M. Van Delft and L. O’Reilly for advice. This work was supported by grants (programmes 257502 and 251608; project 384404) and fellowships from the NHMRC (Canberra), NCI (NIH, CA 80188, CA 43540), Leukemia and Lymphoma Society of America (SCOR grant 7015), JDRF/NHMRC, Cancer Council Victoria, Leukemia Foundation of Australia, Swiss National Science Foundation (T.K. and U.N.), Novartis Jubilaeumsstiftung (U.N.), HepatoSys programme (BMBF), German Jose Carreras Leukemia Foundation (DJCLS R 06/09), Spemann Graduate School of Biology and Medicine (GSC-4), DFG (to C.B.) and Dr. Mildred-Scheel Stiftung/Deutsche Krebshilfe (P.J.J.).

Author Contributions P.J.J. and T.K. designed and performed the experiments; A.S. designed experiments and supervised the project; S.G., D.G., M.D.M., J.S. and U.N. performed some experiments; and D.C.S.H., P.B., C.B. and H.E.T. generated essential tools.

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Author notes

  1. Thomas Kaufmann

    Present address: Present address: Institute of Pharmacology, University of Bern, Bern, CH-3010, Switzerland.,

  2. Andreas Strasser and Thomas Kaufmann: These authors contributed equally to this work.

Authors and Affiliations

  1. The Walter and Eliza Hall Institute of Medical Research,,

    Philipp J. Jost, Stephanie Grabow, Daniel Gray, David C. S. Huang, Philippe Bouillet, Andreas Strasser & Thomas Kaufmann

  2. Department of Medical Biology, Melbourne University, Parkville, Victoria 3050, Australia,

    Stephanie Grabow & Mark D. McKenzie

  3. St Vincent’s Institute of Medical Research, Fitzroy, Victoria 3065, Australia ,

    Mark D. McKenzie & Helen E. Thomas

  4. Institute of Biochemistry, LaTrobe University, Bundoora, Victoria 3086, Australia ,

    Ueli Nachbur & John Silke

  5. Institute of Molecular Medicine and Cell Research, Centre for Biochemistry and Molecular Cell Research, Freiburg, D79104, Germany ,

    Christoph Borner

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Jost, P., Grabow, S., Gray, D. et al. XIAP discriminates between type I and type II FAS-induced apoptosis. Nature 460, 1035–1039 (2009). https://doi.org/10.1038/nature08229

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