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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{dagger}

Jan Liman,1,{ddagger} Sundar Ganesan,2,{ddagger} Christoph P. Dohm,1 Stan Krajewski,3 John C. Reed,3 Mathias Bähr,1 Fred S. Wouters,2*,{ddagger} and Pawel Kermer1*,{ddagger}

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 (BAG{Delta}C) 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 BAG{Delta}C compared to wild-type cells. Interestingly, in contrast to the nuclear and cytosolic localizations of full-length BAG1, BAG{Delta}C was expressed exclusively in the cytosol. Furthermore, cells expressing BAG{Delta}C 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 Fred S. Wouters: Cell Biophysics Group, European Neuroscience Institute Göttingen, Waldweg 33, 37075 Göttingen, Germany. Phone: 0049-551-3912368. Fax: 0049-551-3912346. E-mail: fred.wouters{at}gwdg.de.

* 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.

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

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

Molecular and Cellular Biology, May 2005, p. 3715-3725, Vol. 25, No. 9
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.9.3715-3725.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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