Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Interaction of Bcl-XL with InsP3R.
Figure 2: Effects of Bcl-XL on InsP3R single-channel activity.
Figure 3: tBid and Bax antagonize the effects of Bcl-XL on InsP3R channel activity.
Figure 4: Interaction of Bcl-XL with InsP3R is essential for Bcl-XL effects on ER Ca2+ regulation and inhibition of apoptosis.
Figure 5: The Bcl-XL–InsP3R interaction modulates [Ca2+]i signalling and mitochondrial NADH levels.

Similar content being viewed by others

Accession codes

Accessions

BINDPlus

References

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

    Article  CAS  Google Scholar 

  2. Vander Heiden, M. G. & Thompson, C. B. Bcl-2 proteins: regulators of apoptosis or of mitochondrial homeostasis? Nature Cell Biol. 1, E209–E216 (1999).

    Article  CAS  Google Scholar 

  3. Krajewski, S. 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).

    CAS  PubMed  Google Scholar 

  4. Distelhorst, C. W. & Shore, G. C. Bcl-2 and calcium: controversy beneath the surface. Oncogene 23, 2875–2880 (2004).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. Breckenridge, D. G., Germain, M., Mathai, J. P., Nguyen, M. & Shore, G. C. Regulation of apoptosis by endoplasmic reticulum pathways. Oncogene 22, 8608–8618 (2003).

    Article  CAS  Google Scholar 

  9. Orrenius, S., Zhivotovsky, B. & Nicotera, P. Regulation of cell death: the calcium-apoptosis link. Nature Rev. Mol. Cell Biol. 4, 552–565 (2003).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Szalai, G., Krishnamurthy, R. & Hajnoczky, G. Apoptosis driven by IP3-linked mitochondrial calcium signals. EMBO J. 18, 6349–6361 (1999).

    Article  CAS  Google Scholar 

  15. Oakes, S. A. 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).

    Article  CAS  Google Scholar 

  16. Chen, R. 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).

    Article  CAS  Google Scholar 

  17. Mak, D. O., McBride, S. & Foskett, J. K. 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).

    Article  CAS  Google Scholar 

  18. Luzzi, V., Sims, C. E., Soughayer, J. S. & Allbritton, N. L. The physiologic concentration of inositol 1,4,5-trisphosphate in the oocytes of Xenopus laevis. J. Biol. Chem. 273, 28657–28662 (1998).

    Article  CAS  Google Scholar 

  19. Korsmeyer, S. J. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  21. Sugawara, H., Kurosaki, M., Takata, M. & Kurosaki, T. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  23. Palmer, A. E., Jin, C., Reed, J. C. & Tsien, R. Y. 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).

    Article  CAS  Google Scholar 

  24. Pinton, P. 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).

    Article  CAS  Google Scholar 

  25. Niiro, H. & Clark, E. A. Regulation of B-cell fate by antigen-receptor signals. Nature Rev. Immunol. 2, 945–956 (2002).

    Article  CAS  Google Scholar 

  26. Doi, T., Motoyama, N., Tokunaga, A. & Watanabe, T. 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).

    Article  CAS  Google Scholar 

  27. Hajnoczky, G., Robb-Gaspers, L. D., Seitz, M. B. & Thomas, A. P. Decoding of cytosolic calcium oscillations in the mitochondria. Cell 82, 415–424 (1995).

  28. Kowaltowski, A. J. & Fiskum, G. Redox mechanisms of cytoprotection by Bcl-2. Antioxid. Redox. Signal. 7, 508–514 (2005).

    Article  CAS  Google Scholar 

  29. Hammerman, P. S., Fox, C. J. & Thompson, C. B. Beginnings of a signal-transduction pathway for bioenergetic control of cell survival. Trends Biochem. Sci. 29, 586–592 (2004).

    Article  CAS  Google Scholar 

  30. Plas, D. R. & Thompson, C. B. Cell metabolism in the regulation of programmed cell death. Trends Endocrinol. Metab. 13, 75–78 (2002).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  32. Haynes, L. P., Tepikin, A. V. & Burgoyne, R. D. 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).

    Article  CAS  Google Scholar 

Download references

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

Authors and Affiliations

Authors

Corresponding author

Correspondence to J. Kevin Foskett.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary figures S1, S2, S3 and S4 (PDF 465 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

White, C., Li, C., Yang, J. et al. The endoplasmic reticulum gateway to apoptosis by Bcl-XL modulation of the InsP3R. Nat Cell Biol 7, 1021–1028 (2005). https://doi.org/10.1038/ncb1302

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1302

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing