Endoplasmic reticulum protein BI-1 regulates Ca2+-mediated bioenergetics to promote autophagy
- Renata Sano1,
- Ying-Chen Claire Hou1,
- Michael Hedvat1,
- Ricardo G. Correa1,
- Chih-Wen Shu1,
- Maryla Krajewska1,
- Paul W. Diaz1,
- Craig M. Tamble1,
- Giovanni Quarato2,
- Roberta A. Gottlieb2,
- Masaya Yamaguchi3,
- Victor Nizet3,4,
- Russell Dahl1,
- David D. Thomas5,
- Stephen W. Tait6,
- Douglas R. Green6,
- Paul B. Fisher7,
- Shu-Ichi Matsuzawa1 and
- John C. Reed1,8
- 1Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA;
- 2BioScience Center, San Diego State University, San Diego, California 92182, USA;
- 3Department of Pediatrics, School of Medicine,
- 4Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, California, 92093 USA;
- 5Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455, USA;
- 6Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 92105, USA;
- 7Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298, USA
Abstract
Autophagy is a lysosomal degradation pathway that converts macromolecules into substrates for energy production during nutrient-scarce conditions such as those encountered in tumor microenvironments. Constitutive mitochondrial uptake of endoplasmic reticulum (ER) Ca2+ mediated by inositol triphosphate receptors (IP3Rs) maintains cellular bioenergetics, thus suppressing autophagy. We show that the ER membrane protein Bax inhibitor-1 (BI-1) promotes autophagy in an IP3R-dependent manner. By reducing steady-state levels of ER Ca2+ via IP3Rs, BI-1 influences mitochondrial bioenergetics, reducing oxygen consumption, impacting cellular ATP levels, and stimulating autophagy. Furthermore, BI-1-deficient mice show reduced basal autophagy, and experimentally reducing BI-1 expression impairs tumor xenograft growth in vivo. BI-1's ability to promote autophagy could be dissociated from its known function as a modulator of IRE1 signaling in the context of ER stress. The results reveal BI-1 as a novel autophagy regulator that bridges Ca2+ signaling between ER and mitochondria, reducing cellular oxygen consumption and contributing to cellular resilience in the face of metabolic stress.
Keywords
Footnotes
-
↵8 Corresponding author.
E-mail reedoffice{at}sanfordburnham.org.
-
Supplemental material is available for this article.
-
Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.184325.111.
- Received November 28, 2011.
- Accepted March 29, 2012.
- Copyright © 2012 by Cold Spring Harbor Laboratory Press