Phosphatidylinositol 4-phosphate is required for translation initiation in Saccharomyces cerevisiae.
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 eIF2alpha. 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.
Cameroni
Elisabetta
E
Department of Microbiology and Molecular Medicine, Centre Médical Universitaire, University of Geneva, 1 rue Michel-Servet, 1211 Geneva, Switzerland.
De Virgilio
Claudio
C
Deloche
Olivier
O
D000730:Androstadienes / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000502:physiology*; D010766:Phosphorylation; D014176:Protein Biosynthesis; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D000077191:Wortmannin
D000730:Androstadienes; D004791:Enzyme Inhibitors; D015852:Eukaryotic Initiation Factor-2; D018129:Phosphatidylinositol Phosphates; C037178:phosphatidylinositol 4-phosphate; D000077191:Wortmannin