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Molecular and Cellular Biology, December 2002, p. 8506-8513, Vol. 22, No. 24
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.24.8506-8513.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Heat Shock Protein 90 Modulates the Unfolded Protein Response by Stabilizing IRE1{alpha}

Monica G. Marcu,1 Melissa Doyle,2 Anne Bertolotti,3,{dagger} David Ron,3 Linda Hendershot,2 and Len Neckers1*

Cell and Cancer Biology Branch, National Cancer Institute, National Institutes of Health, Rockville, Maryland 20850,1 St. Jude Children's Research Hospital, Memphis, Tennessee 38105,2 Skirball Institute, New York University, New York, New York 100163

Received 15 August 2002/ Accepted 16 September 2002

The molecular chaperone HSP90 regulates stability and function of multiple protein kinases. The HSP90-binding drug geldanamycin interferes with this activity and promotes proteasome-dependent degradation of most HSP90 client proteins. Geldanamycin also binds to GRP94, the HSP90 paralog located in the endoplasmic reticulum (ER). Because two of three ER stress sensors are transmembrane kinases, namely IRE1{alpha} and PERK, we investigated whether HSP90 is necessary for the stability and function of these proteins. We found that HSP90 associates with the cytoplasmic domains of both kinases. Both geldanamycin and the HSP90-specific inhibitor, 514, led to the dissociation of HSP90 from the kinases and a concomitant turnover of newly synthesized and existing pools of these proteins, demonstrating that the continued association of HSP90 with the kinases was required to maintain their stability. Further, the previously reported ability of geldanamycin to stimulate ER stress-dependent transcription apparently depends on its interaction with GRP94, not HSP90, since geldanamycin but not 514 led to up-regulation of BiP. However, this effect is eventually superseded by HSP90-dependent destabilization of unfolded protein response signaling. These data establish a role for HSP90 in the cellular transcriptional response to ER stress and demonstrate that chaperone systems on both sides of the ER membrane serve to integrate this signal transduction cascade.

* Corresponding author. Mailing address: 9610 Medical Ctr. Dr., Suite 300, Rockville, MD 20850. Phone: (301) 402-3128, ext. 318. Fax: (301) 402-4422. E-mail: len{at}helix.nih.gov.

{dagger} Present address: INSERM, Laboratoire de Genetique Moleculaire, UMR8541 du CNRS, Ecole Normale Superieure, 75005 Paris, France.

Molecular and Cellular Biology, December 2002, p. 8506-8513, Vol. 22, No. 24
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.24.8506-8513.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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