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PNAS 97 (6): 2597-2602

Copyright © 2000 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / CELL BIOLOGY

BAR: An apoptosis regulator at the intersection of caspases and Bcl-2 family proteins

Hong Zhang*, Qunli Xu*, Stanislaw Krajewski, Maryla Krajewska, Zhihua Xie, Sally Fuess, Shinichi Kitada, Krzysztof Pawlowski, Adam Godzik, and John C. Reed{dagger}

Program on Apoptosis and Cell Death Regulation, The Burnham Institute, La Jolla, CA 92037

Accepted for publication December 27, 1999.

Received for publication October 26, 1999.

Abstract: Two major pathways for induction of apoptosis have been identified—intrinsic and extrinsic. The extrinsic pathway is represented by tumor necrosis factor family receptors, which utilize protein interaction modules known as death domains and death effector domains (DEDs) to assemble receptor signaling complexes that recruit and activate certain caspase-family cell death proteases, namely procaspases-8 and -10. The intrinsic pathway for apoptosis involves the participation of mitochondria, which release caspase-activating proteins. Bcl-2 family proteins govern this mitochondria-dependent apoptosis pathway, with proteins such as Bax functioning as inducers and proteins such as Bcl-2 and Bcl-XL serving as suppressors of cell death. An apoptosis regulator, BAR, was identified by using a yeast-based screen for inhibitors of Bax-induced cell death. The BAR protein contains a SAM domain, which is required for its interactions with Bcl-2 and Bcl-XL and for suppression of Bax-induced cell death in both mammalian cells and yeast. In addition, BAR contains a DED-like domain responsible for its interaction with DED-containing procaspases and suppression of Fas-induced apoptosis. Furthermore, BAR can bridge procaspase-8 and Bcl-2 into a protein complex. The BAR protein is anchored in intracellular membranes where Bcl-2 resides. BAR therefore may represent a scaffold protein capable of bridging two major apoptosis pathways.

* H.Z. and Q.X. contributed equally to this work.

{dagger} To whom reprint requests should be addressed at: The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037. E-mail: jreed{at}burnham-inst.org.

Communicated by Erkki Ruoslahti, The Burnham Institute, La Jolla, CA

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