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