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J. Biol. Chem., Vol. 281, Issue 50, 38139-38149, December 15, 2006

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Phosphatidylinositol 4-Phosphate Is Required for Translation Initiation in Saccharomyces cerevisiae^*

From the Department of Microbiology and Molecular Medicine, Centre Medical Universitaire, University of Geneva, 1211 Geneva, Switzerland

The small natural product wortmannin inhibits protein synthesis by modulating several phosphatidylinositol (PI) metabolic pathways. A primary target of wortmannin in yeast is the plasma membrane-associated PI 4-kinase (PI4K) Stt4p, which is required for actin cytoskeleton organization. Here we show that wortmannin treatment or inactivation of Stt4p, but not disorganization of the actin cytoskeleton per se, leads to a rapid attenuation of translation initiation. Interestingly, inactivation of Pik1p, a wortmannin-insensitive, functionally distinct PI4K, implicated in the regulation of Golgi functions and secretion, also results in severe translation initiation defects with a marked increase of the phosphorylation of the translation initiation factor eIF2. Because wortmannin largely phenocopies the effects of rapamycin (e.g. it triggers nuclear accumulation of Gln3p), it likely also inhibits the PI kinase-related, target of rapamycin (TOR) kinases. Importantly, however, neither inactivation of Stt4p nor Pik1p significantly affects TOR-controlled readouts other than translation initiation, indicating that these PI4Ks do not simply function upstream of TOR. Together, our results reveal the existence of a novel translation initiation control mechanism in yeast that is tightly coupled to the synthesis of distinct PI4P pools.

Received for publication, February 3, 2006 , and in revised form, September 8, 2006.

^* This work was supported by grants from the Swiss National Science Foundation and Canton of Geneva Grants FN-31-654039 (to C. Georgopoulos) and FN-PP00A-106754 (to C. D. V.). 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.

¹ To whom correspondence should be addressed: Centre Médical Universitaire, Université de Genève, 1, rue Michel-Servet, 1211 Genève, Switzerland. Tel.: 41-22-379-55-10; Fax: 41-22-379-55-02; E-mail: olivier.deloche{at}medecine.unige.ch.

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