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

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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References

  1. Nagata, S. FAS ligand-induced apoptosis. Annu. Rev. Genet. 33, 29–55 (1999)

    Article  CAS  Google Scholar 

  2. Krammer, P. H. CD95’s deadly mission in the immune system. Nature 407, 789–795 (2000)

    Article  ADS  CAS  Google Scholar 

  3. Peter, M. E. et al. The CD95 receptor: apoptosis revisited. Cell 129, 447–450 (2007)

    Article  CAS  Google Scholar 

  4. Strasser, A., Jost, P. J. & Nagata, S. The many roles of FAS receptor signaling in the immune system. Immunity 30, 180–192 (2009)

    Article  CAS  Google Scholar 

  5. Wang, K., Yin, X.-M., Chao, D. T., Milliman, C. L. & Korsmeyer, S. J. BID: a novel BH3 domain-only death agonist. Genes Dev. 10, 2859–2869 (1996)

    Article  CAS  Google Scholar 

  6. Yin, X.-M. et al. Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis. Nature 400, 886–891 (1999)

    Article  ADS  CAS  Google Scholar 

  7. Kaufmann, T. et al. The BH3-only protein Bid is dispensable for DNA damage- and replicative stress-induced apoptosis or cell-cycle arrest. Cell 129, 423–433 (2007)

    Article  CAS  Google Scholar 

  8. McKenzie, M. D. et al. Proapoptotic BH3-only protein Bid is essential for death receptor-induced apoptosis of pancreatic β-cells. Diabetes 57, 1284–1292 (2008)

    Article  CAS  Google Scholar 

  9. Holcik, M. & Korneluk, R. G. XIAP, the guardian angel. Nature Rev. Mol. Cell Biol. 2, 550–556 (2001)

    Article  CAS  Google Scholar 

  10. Vaux, D. L. & Silke, J. IAPs, RINGs and ubiquitylation. Nature Rev. Mol. Cell Biol. 6, 287–297 (2005)

    Article  CAS  Google Scholar 

  11. Du, C., Fang, M., Li, Y., Li, L. & Wang, X. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 102, 33–42 (2000)

    Article  CAS  Google Scholar 

  12. Verhagen, A. M. et al. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing inhibitor of apoptosis (IAP) proteins. Cell 102, 43–53 (2000)

    Article  CAS  Google Scholar 

  13. Huang, D. C. et al. Activation of Fas by FasL induces apoptosis by a mechanism that cannot be blocked by Bcl-2 or Bcl-xL . Proc. Natl Acad. Sci. USA 96, 14871–14876 (1999)

    Article  ADS  CAS  Google Scholar 

  14. Ogasawara, J. et al. Lethal effect of the anti-Fas antibody in mice. Nature 364, 806–809 (1993)

    Article  ADS  CAS  Google Scholar 

  15. Malhi, H. & Gores, G. J. Cellular and molecular mechanisms of liver injury. Gastroenterology 134, 1641–1654 (2008)

    Article  CAS  Google Scholar 

  16. Varfolomeev, E. E. et al. Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1, and DR3 and is lethal prenatally. Immunity 9, 267–276 (1998)

    Article  CAS  Google Scholar 

  17. Newton, K., Harris, A. W., Bath, M. L., Smith, K. G. C. & Strasser, A. A dominant interfering mutant of FADD/Mort1 enhances deletion of autoreactive thymocytes and inhibits proliferation of mature T lymphocytes. EMBO J. 17, 706–718 (1998)

    Article  CAS  Google Scholar 

  18. Scaffidi, C. et al. Two CD95 (APO-1/Fas) signaling pathways. EMBO J. 17, 1675–1687 (1998)

    Article  CAS  Google Scholar 

  19. Algeciras-Schimnich, A. et al. Molecular ordering of the initial signaling events of CD95. Mol. Cell. Biol. 22, 207–220 (2002)

    Article  CAS  Google Scholar 

  20. Li, S. et al. Relief of extrinsic pathway inhibition by the Bid-dependent mitochondrial release of Smac in Fas-mediated hepatocyte apoptosis. J. Biol. Chem. 277, 26912–26920 (2002)

    Article  CAS  Google Scholar 

  21. Liu, X., Zou, H., Slaughter, C. & Wang, X. DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. Cell 89, 175–184 (1997)

    Article  CAS  Google Scholar 

  22. Enari, M. et al. A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 391, 43–50 (1998)

    Article  ADS  CAS  Google Scholar 

  23. Conte, D., Liston, P., Wong, J. W., Wright, K. E. & Korneluk, R. G. Thymocyte-targeted overexpression of xiap transgene disrupts T lymphoid apoptosis and maturation. Proc. Natl Acad. Sci. USA 98, 5049–5054 (2001)

    Article  ADS  CAS  Google Scholar 

  24. Harlin, H., Reffey, S. B., Duckett, C. S., Lindsten, T. & Thompson, C. B. Characterization of XIAP-deficient mice. Mol. Cell. Biol. 21, 3604–3608 (2001)

    Article  CAS  Google Scholar 

  25. Hao, Z. et al. Specific ablation of the apoptotic functions of cytochrome c reveals a differential requirement for cytochrome c and Apaf-1 in apoptosis. Cell 121, 579–591 (2005)

    Article  CAS  Google Scholar 

  26. Lakhani, S. A. et al. Caspases 3 and 7: key mediators of mitochondrial events of apoptosis. Science 311, 847–851 (2006)

    Article  ADS  CAS  Google Scholar 

  27. Varfolomeev, E. et al. IAP antagonists induce autoubiquitination of c-IAPs, NF-κB activation, and TNFα-dependent apoptosis. Cell 131, 669–681 (2007)

    Article  CAS  Google Scholar 

  28. Vince, J. E. et al. IAP antagonists target cIAP1 to induce TNFα-dependent apoptosis. Cell 131, 682–693 (2007)

    Article  CAS  Google Scholar 

  29. Petersen, S. L. et al. Autocrine TNFα signaling renders human cancer cells susceptible to Smac-mimetic-induced apoptosis. Cancer Cell 12, 445–456 (2007)

    Article  CAS  Google Scholar 

  30. Gaither, A. et al. A Smac mimetic rescue screen reveals roles for inhibitor of apoptosis proteins in tumor necrosis factor-α signaling. Cancer Res. 67, 11493–11498 (2007)

    Article  CAS  Google Scholar 

  31. Kaufmann, T. et al. The BH3-only protein Bid is dispensable for DNA damage- and replicative stress-induced apoptosis or cell-cycle arrest. Cell 129, 423–433 (2007)

    Article  CAS  Google Scholar 

  32. Olayioye, M. A. et al. XIAP-deficiency leads to delayed lobuloalveolar development in the mammary gland. Cell Death Differ. 12, 87–90 (2005)

    Article  CAS  Google Scholar 

  33. O’Reilly, L. A. et al. Modifications and intracellular trafficking of FADD/MORT1 and caspase-8 after stimulation of T lymphocytes. Cell Death Differ. 11, 724–736 (2004)

    Article  Google Scholar 

  34. Waanders, G. A. & Boyd, R. L. The effects of interleukin 2 on early and late thymocyte differentiation in foetal thymus organ culture. Int. Immunol. 2, 461–468 (1990)

    Article  CAS  Google Scholar 

  35. McKenzie, M. D. et al. Perforin and Fas induced by IFN and TNF mediate beta cell death by OT-I CTL. Int. Immunol. 18, 837–846 (2006)

    Article  CAS  Google Scholar 

  36. Nicoletti, I., Migliorati, G., Pagliacci, M. C., Grignani, F. & Riccardi, C. A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J. Immunol. Methods 139, 271–279 (1991)

    Article  CAS  Google Scholar 

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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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Correspondence to Andreas Strasser or Thomas Kaufmann.

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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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