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The endoplasmic reticulum gateway to apoptosis by Bcl-XL modulation of the InsP3R

Nature Cell Biology volume 7, pages 10211028 (2005) | Download Citation

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  • A Corrigendum to this article was published on 01 March 2006

Abstract

Members of the Bcl-2 protein family modulate outer mitochondrial membrane permeability to control apoptosis1,2. However, these proteins also localize to the endoplasmic reticulum (ER), the functional significance of which is controversial3,4. Here we provide evidence that anti-apoptotic Bcl-2 proteins regulate the inositol 1,4,5-trisphosphate receptor (InsP3R) ER Ca2+ release channel resulting in increased cellular apoptotic resistance and enhanced mitochondrial bioenergetics. Anti-apoptotic Bcl-XL interacts with the carboxyl terminus of the InsP3R and sensitizes single InsP3R channels in ER membranes to low [InsP3], enhancing Ca2+ and InsP3-dependent regulation of channel activity in vitro and in vivo, reducing ER Ca2+ content and stimulating mitochondrial energetics. The pro-apoptotic proteins Bax and tBid antagonize this effect by blocking the biochemical interaction of Bcl-XL with the InsP3R. These data support a novel model in which Bcl-XL is a direct effector of the InsP3R, increasing its sensitivity to InsP3 and enabling ER Ca2+ release to be more sensitively coupled to extracellular signals. As a consequence, cells are protected against apoptosis by a more sensitive and dynamic coupling of ER to mitochondria through Ca2+-dependent signal transduction that enhances cellular bioenergetics and preserves survival.

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References

  1. 1.

    et al. Proapoptotic BAX and BAK: A requisite gateway to mitochondrial dysfunction and death. Science 292, 727–730 (2001).

  2. 2.

    & Bcl-2 proteins: regulators of apoptosis or of mitochondrial homeostasis? Nature Cell Biol. 1, E209–E216 (1999).

  3. 3.

    et al. Investigation of the subcellular distribution of the Bcl-2 oncoprotein - residence in the nuclear envelope, endoplasmic reticulum, and outer mitochondrial membranes. Cancer Res. 53, 4701–4714 (1993).

  4. 4.

    & Bcl-2 and calcium: controversy beneath the surface. Oncogene 23, 2875–2880 (2004).

  5. 5.

    et al. Bax directly induces release of cytochrome c from isolated mitochondria. Proc. Natl Acad. Sci. USA 95, 4997–5002 (1998).

  6. 6.

    et al. Inhibition of Bax channel-forming activity by Bcl-2. Science 277, 370–372 (1997).

  7. 7.

    et al. Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis. J. Cell Biol. 162, 59–69 (2003).

  8. 8.

    , , , & Regulation of apoptosis by endoplasmic reticulum pathways. Oncogene 22, 8608–8618 (2003).

  9. 9.

    , & Regulation of cell death: the calcium-apoptosis link. Nature Rev. Mol. Cell Biol. 4, 552–565 (2003).

  10. 10.

    et al. BAX and BAK regulation of endoplasmic reticulum Ca2+: A control point for apoptosis. Science 300, 135–139 (2003).

  11. 11.

    et al. Calcium and apoptosis: facts and hypotheses. Oncogene 22, 8619–8627 (2003).

  12. 12.

    Mitochondria and calcium: from cell signalling to cell death. J. Physiol. 529, 57–68 (2000).

  13. 13.

    & Cross-talk between two cysteine protease families. Activation of caspase-12 by calpain in apoptosis. J. Cell Biol. 150, 887–894 (2000).

  14. 14.

    , & Apoptosis driven by IP3-linked mitochondrial calcium signals. EMBO J. 18, 6349–6361 (1999).

  15. 15.

    et al. Proapoptotic BAX and BAK regulate the type 1 inositol trisphosphate receptor and calcium leak from the endoplasmic reticulum. Proc. Natl Acad. Sci. USA 102, 105–110 (2005).

  16. 16.

    et al. Bcl-2 functionally interacts with inositol 1,4,5-trisphosphate receptors to regulate calcium release from the ER in response to inositol 1,4,5-trisphosphate. J. Cell Biol. 166, 193–203 (2004).

  17. 17.

    , & Inositol 1,4,5-trisphosphate activation of inositol trisphosphate receptor Ca2+ channel by ligand tuning of Ca2+ inhibition. Proc. Natl Acad. Sci. USA 95, 15821–15825 (1998).

  18. 18.

    , , & The physiologic concentration of inositol 1,4,5-trisphosphate in the oocytes of Xenopus laevis. J. Biol. Chem. 273, 28657–28662 (1998).

  19. 19.

    et al. Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c. Cell Death Differ. 7, 1166–1173 (2000).

  20. 20.

    et al. Bcl-xL forms an ion channel in synthetic lipid membranes. Nature 385, 353–357 (1997).

  21. 21.

    , , & Genetic evidence for involvement of type 1, type 2 and type 3 inositol 1,4,5-trisphosphate receptors in signal transduction through the B-cell antigen receptor. EMBO J. 16, 3078–3088 (1997).

  22. 22.

    et al. Bcl-2 decreases the free Ca2+ concentration within the endoplasmic reticulum. Proc. Natl Acad. Sci. USA 97, 5723–5728 (2000).

  23. 23.

    , , & Bcl-2-mediated alterations in endoplasmic reticulum Ca2+ analyzed with an improved genetically encoded fluorescent sensor. Proc. Natl Acad. Sci. USA 101, 17404–17409 (2004).

  24. 24.

    et al. Reduced loading of intracellular Ca2+ stores and downregulation of capacitative Ca2+ influx in Bcl-2-overexpressing cells. J. Cell Biol. 148, 857–862 (2000).

  25. 25.

    & Regulation of B-cell fate by antigen-receptor signals. Nature Rev. Immunol. 2, 945–956 (2002).

  26. 26.

    , , & Death signals from the B cell antigen receptor target mitochondria, activating necrotic and apoptotic death cascades in a murine B cell line, WEHI-231. Int. Immunol. 11, 933–941 (1999).

  27. 27.

    , , & Decoding of cytosolic calcium oscillations in the mitochondria. Cell 82, 415–424 (1995).

  28. 28.

    & Redox mechanisms of cytoprotection by Bcl-2. Antioxid. Redox. Signal. 7, 508–514 (2005).

  29. 29.

    , & Beginnings of a signal-transduction pathway for bioenergetic control of cell survival. Trends Biochem. Sci. 29, 586–592 (2004).

  30. 30.

    & Cell metabolism in the regulation of programmed cell death. Trends Endocrinol. Metab. 13, 75–78 (2002).

  31. 31.

    , & Use of La3+ to distinguish activity of the plasmalemmal Ca2+ pump from Na+/Ca2+ exchange in arterial myocytes. Cell Calcium 21, 31–41 (1997).

  32. 32.

    , & Calcium-binding protein 1 is an inhibitor of agonist-evoked, inositol 1,4,5-trisphosphate-mediated calcium signaling. J. Biol. Chem. 279, 547–555 (2004).

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Acknowledgements

We are grateful to D. Newmeyer for the tBid expression plasmid, and S. Joseph and A. Tanimura for InsP3R antibodies. C.W. and C.L. contributed equally to the major intellectual and technical aspects of the studies. J.Y. and N.B.P. contributed molecular biological and electrophysiology support, respectively. M.M. performed the NADH assays. C.B.T. and J.K.F. contributed ideas and assisted in the preparation of the text. This work was supported by NIH grants (C.B.T. and J.K.F.), an NIH Training Grant (C.L.), an American Heart Association Fellowship (C.W.) and the Abramson Family Cancer Research Institute.

Author information

Author notes

    • Carl White
    •  & Chi Li

    These authors contributed equally to this work.

Affiliations

  1. Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104, USA.

    • Carl White
    • , Jun Yang
    • , Nataliya B. Petrenko
    •  & J. Kevin Foskett
  2. Department of Cancer Biology, Abramson Family Cancer Research Institute, Philadelphia, PA 19104, USA.

    • Chi Li
    • , Muniswamy Madesh
    •  & Craig B. Thompson
  3. Institute for Environmental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

    • Muniswamy Madesh
  4. Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.

    • J. Kevin Foskett

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to J. Kevin Foskett.

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DOI

https://doi.org/10.1038/ncb1302

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