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J. Biol. Chem., Vol. 280, Issue 32, 28989-28996, August 12, 2005

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Protein Phosphatase 5 Is a Negative Modulator of Heat Shock Factor 1^*

Renaud Conde, Johnny Xavier, Christine McLoughlin¶, Michael Chinkers||, and Nick Ovsenek**

From the Department of Anatomy and Cell Biology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada and the ^||Department of Pharmacology, University of South Alabama, Mobile, Alabama 36688

The major stress protein transcription factor, heat shock factor (HSF1), is tightly regulated through a multilayered activation-deactivation process involving oligomerization, post-translational modification, and interaction with the heat shock protein (Hsp90)-containing multichaperone complex. Conditions of proteotoxic stress, such as heat shock, trigger reversible assembly of latent HSF1 monomers into DNA-binding homotrimers that bind with high affinity to cognate heat shock elements. Transactivation is a second and independently regulated function of HSF1 that is accompanied by hyperphosphorylation and appears to involve a number of signaling events. Association of HSF1 with Hsp90 chaperone complexes provides additional regulatory complexity, however, not all the co-chaperones have been identified, and the specific molecular interactions throughout the activation/deactivation pathway remain to be determined. Here we demonstrate that protein phosphatase 5 (PP5), a tetratricopeptide domain-containing component of Hsp90-steroid receptor complexes, functions as a negative modulator of HSF1 activity. Physical interactions between PP5 and HSF1-Hsp90 complexes were observed in co-immunoprecipitation and gel mobility supershift experiments. Overexpression of PP5 or activation of endogenous phosphatase activity resulted in diminished HSF1 DNA binding and transcriptional activities, and accelerated recovery. Conversely, microinjection of PP5 antibodies, or inhibition of its phosphatase activity in vivo, significantly delayed trimer disassembly after heat shock. Inhibition of PP5 activity did not activate HSF1 in unstressed cells. These results indicate that PP5 is a negative modulator of HSF1 activity.

Received for publication, April 1, 2005 , and in revised form, June 17, 2005.

^* This work was supported in part Canadian Institutes of Health Research Grant CIHR MOP-42367 and a Natural Sciences and Engineering Research Council Discovery Grant (to N. O.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a Postdoctoral Fellowship from the Health Sciences Utilization Research Council of Saskatchewan.

^¶ Supported by an Natural Sciences and Engineering Research Council Post Graduate (Masters) scholarship.

^** To whom correspondence should be addressed: Dept. of Anatomy and Cell Biology, College of Medicine, University of Saskatchewan, 107 Wiggins Rd., Saskatoon, Saskatchewan S7N 5E5, Canada. Tel.: 306-966-4069; Fax: 306-966-4298; E-mail: ovsenekn{at}duke.usask.ca.

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