Nature Cell Biology
7, 1021 - 1028 (2005)
Published online: 18 September 2005; | doi:10.1038/ncb1302
There is a Corrigendum (March 2006) associated with this Letter.
The endoplasmic reticulum gateway to apoptosis by Bcl-XL modulation of the InsP3RCarl White1, 5, Chi Li2, 5, Jun Yang1, Nataliya B. Petrenko1, Muniswamy Madesh2, 3, Craig B. Thompson2
& J. Kevin Foskett1, 41
Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104, USA. 2
Department of Cancer Biology, Abramson Family Cancer Research Institute, Philadelphia, PA 19104, USA. 3
Institute for Environmental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. 4
Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA. 5
These authors contributed equally to this work.
Correspondence should be addressed to J. Kevin Foskett foskett@mail.med.upenn.edu 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.
MORE ARTICLES LIKE THIS These links to content published by NPG are automatically generated.
|
