Dual control of inositol transport in Saccharomyces cerevisiae by irreversible inactivation of permease and regulation of permease synthesis by INO2, INO4, and OPI1.

Uptake of inositol by Saccharomyces cerevisiae is regulated through transcriptional control of the gene that encodes the major inositol permease, ITR1 (Nikawa, J., Tsukagoshi, Y., and Yamashita, S. (1991) J. Biol. Chem. 266, 11184-11191). ITR1 mRNA abundance decreases when cells are transferred from medium without inositol to medium with inositol. Here we demonstrate that the mechanism of transcriptional regulation of ITR1 is through the action of the INO2, INO4 and OPI1 genes. INO2 and INO4 are required for derepressed levels of ITR1 mRNA, and OPI1 is necessary for repression of transcript levels in response to inositol. The INO2, INO4, and OPI1 genes thus coordinate uptake of inositol to endogenous inositol biosynthesis and to phospholipid biosynthesis. Repression of transcription of ITR1 also requires ongoing synthesis of phosphatidylcholine, defining an additional link between synthesis of phospholipids and regulation of inositol uptake. Analysis showed that the INO1 gene, encoding a key enzyme in the inositol biosynthetic pathway, responded to decreases in permease activity with a graduated increase in the level of INO1 mRNA. We also found that, in addition to the transcriptional regulation, inositol permease activity is regulated by irreversible inactivation. Inactivation of the ITR1 permease occurs in response to the presence of inositol and involves a change in the functional half-life of the protein.