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Molecular and Cellular Biology, May 2005, p. 3715-3725, Vol. 25, No. 9
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.9.3715-3725.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Interaction of BAG1 and Hsp70 Mediates Neuroprotectivity and Increases Chaperone Activity

Jan Liman,^1, Sundar Ganesan,^2, Christoph P. Dohm,¹ Stan Krajewski,³ John C. Reed,³ Mathias Bähr,¹ Fred S. Wouters,^2*, and Pawel Kermer^1*,

Neurologische Klinik, Universität Göttingen,¹ Cell Biophysics Group, European Neuroscience Institute Göttingen, Göttingen, Germany,² The Burnham Institute, La Jolla, California³

Received 17 September 2004/ Returned for modification 20 October 2004/ Accepted 19 January 2005

It was recently shown that Bcl-2-associated athanogene 1 (BAG1) is a potent neuroprotectant as well as a marker of neuronal differentiation. Since there appears to exist an equilibrium within the cell between BAG1 binding to heat shock protein 70 (Hsp70) and BAG1 binding to Raf-1 kinase, we hypothesized that changing BAG1 binding characteristics might significantly alter BAG1 function. To this end, we compared rat CSM14.1 cells and human SHSY-5Y cells stably overexpressing full-length BAG1 or a deletion mutant (BAGC) no longer capable of binding to Hsp70. Using a novel yellow fluorescent protein-based foldase biosensor, we demonstrated an upregulation of chaperone in situ activity in cells overexpressing full-length BAG1 but not in cells overexpressing BAGC compared to wild-type cells. Interestingly, in contrast to the nuclear and cytosolic localizations of full-length BAG1, BAGC was expressed exclusively in the cytosol. Furthermore, cells expressing BAGC were no longer protected against cell death. However, they still showed accelerated neuronal differentiation. Together, these results suggest that BAG1-induced activation of Hsp70 is important for neuroprotectivity, while BAG1-dependent modulation of neuronal differentiation in vitro is not.

* Corresponding author. Mailing address for Pawel Kermer: Neurologische Klinik, Universität Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany. Phone: 49-551-394927. Fax: 49-551-3914302. E-mail: pkermer{at}gwdg.de.

Supplemental material for this article may be found at http://mcb.asm.org/.

J.L., S.G., F.S.W., and P.K. contributed equally to this work.

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