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J. Biol. Chem., Vol. 278, Issue 36, 33887-33895, September 5, 2003

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The Immunosuppressant FK506 Uncovers a Positive Regulatory Cross-talk between the Hog1p and Gcn2p Pathways^*

Carlos J. Rodriguez-Hernandez   ¶, Isabel Sanchez-Perez  || **, Rosario Gil-Mascarell , Abigail Rodríguez-Afonso , Armando Torres , Rosario Perona || and José R. Murguía  

From the Research Unit, Hospital Universitario de Canarias, Ofra s/n-La Cuesta, 38320-La Laguna and the ^||Instituto de Investigaciones Biomédicas (CSIC), C/Arturo Duperier 4, 28029-Madrid, Spain

The immunosuppressant Tacrolimus (FK506) has increased the survival rates of organ transplantation. FK506 exerts its immunosuppressive effect by inhibition of the protein phosphatase calcineurin in activated T-cells. Unfortunately, FK506 therapy is associated with undesired non-therapeutic effects involving targets other than calcineurin. To identify these targets we have addressed FK506 cellular toxicity in budding yeast. We show that FK506 increased cell sensitivity upon osmotic challenge independently of calcineurin and the FK506-binding proteins Fpr1p, -2p, -3p, and -4p. FK506 also induced strong amino acid starvation and activation of the general control (GCN) pathway. Tryptophan prototrophy or excess tryptophan overcame FK506 toxicity, showing that tryptophan deprivation mediated this effect. Mutation of the GCN3 and -4 genes partially alleviated FK506 toxicity, suggesting that activation of the GCN pathway by FK506 was also involved in osmotic tolerance. FK506 enhanced osmotic stress-dependent Hog1p kinase phosphorylation that was not accompanied by induction of a Hog1p-dependent reporter. Interestingly, deletion of the GCN2 gene suppressed FK506-dependent Hog1p hyperphosphorylation and restored Hog1p-dependent reporter activity. Conversely, deletion of the HOG1 gene impaired FK506-dependent activation of Gcn2p kinase and translation of a GCN4-LacZ reporter, highlighting functional cross-talk between the Gcn2p and Hog1p protein kinases. Taken together, these data demonstrate that both FK506-induced amino acid starvation and activation of the GCN pathway contribute to cell sensitivity to osmotic stress and reveal a positive regulatory loop between the Hog1p and Gcn2p pathways. Given the conserved nature of Gcn2p and Hog1p pathways, this mechanism of FK506 toxicity could be relevant to the non-therapeutic effects of FK506 therapy.

Received for publication, May 19, 2003 , and in revised form, June 13, 2003.

^* This study was supported by Grants 00/0862, 01/1094, and 01/1626 from the Fondo de Investigaciones Sanitarias and by Grant 1FD87-1781 from FEDER. 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.

Both authors contributed equally to this work.

^¶ Fellow of the Fondo de Investigaciones Sanitarias.

^** Fellow of the Comunidad Autonoma de Madrid.

Currently sponsored as an investigator by the Fondo de Investigaciones Sanitarias. To whom correspondence should be addressed. Tel.: 34-922319338; Fax: 34-922319412; E-mail: jmurguia{at}hecit.es.

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