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Molecular and Cellular Biology, December 1999, p. 8422-8432, Vol. 19, No. 12
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Hsp90 Binds and Regulates the Ligand-Inducible alpha  Subunit of Eukaryotic Translation Initiation Factor Kinase Gcn2

Olivier Donzé and Didier Picard*

Département de Biologie Cellulaire, Université de Genève, Sciences III, CH-1211 Geneva 4, Switzerland

Received 29 January 1999/Returned for modification 17 March 1999/Accepted 7 September 1999

The protein kinase Gcn2 stimulates translation of the yeast transcription factor Gcn4 upon amino acid starvation. Using genetic and biochemical approaches, we show that Gcn2 is regulated by the molecular chaperone Hsp90 in budding yeast Saccharomyces cerevisiae. Specifically, we found that (i) several Hsp90 mutant strains exhibit constitutive expression of a GCN4-lacZ reporter plasmid; (ii) Gcn2 and Hsp90 form a complex in vitro as well as in vivo; (iii) the specific inhibitors of Hsp90, geldanamycin and macbecin I, enhance the association of Gcn2 with Hsp90 and inhibit its kinase activity in vitro; (iv) in vivo, macbecin I strongly reduces the levels of Gcn2; (v) in a strain expressing the temperature-sensitive Hsp90 mutant G170D, both the accumulation and activity of Gcn2 are abolished at the restrictive temperature; and (vi) the Hsp90 cochaperones Cdc37, Sti1, and Sba1 are required for the response to amino acid starvation. Taken together, these data identify Gcn2 as a novel target for Hsp90, which plays a crucial role for the maturation and regulation of Gcn2.

* Corresponding author. Mailing address: Département de Biologie Cellulaire, Université de Genève, Sciences III, 30, quai Ernest-Ansermet, CH-1211 Geneva 4, Switzerland. Phone: 41 22 702 6813. Fax: 41 22 702 6442. E-mail: Picard{at}cellbio.unige.ch.

Molecular and Cellular Biology, December 1999, p. 8422-8432, Vol. 19, No. 12
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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