The intersection between stress responses and inositol pyrophosphates in Saccharomyces cerevisiae.

Saccharomyces cerevisiae adapts to oxidative, osmotic stress and nutrient deprivation through transcriptional changes, decreased proliferation, and entry into other developmental pathways such as pseudohyphal formation and sporulation. Inositol pyrophosphates are necessary for these cellular responses. Inositol pyrophosphates are molecules composed of the phosphorylated myo-inositol ring that carries one or more diphosphates. Mutations in the enzymes that metabolize these molecules lead to altered patterns of stress resistance, altered morphology, and defective sporulation. Mechanisms to alter the synthesis of inositol pyrophosphates have been recently described, including inhibition of enzyme activity by oxidation and by phosphorylation. Cells with increased levels of 5-diphosphoinositol pentakisphosphate have increased nuclear localization of Msn2 and Gln3. The altered localization of these factors is consistent with the partially induced environmental stress response and increased expression of genes under the control of Msn2/4 and Gln3. Other transcription factors may also exhibit increased nuclear localization based on increased expression of their target genes. These transcription factors are each regulated by TORC1, suggesting that TORC1 may be inhibited by inositol pyrophosphates. Inositol pyrophosphates affect stress responses in other fungi (Aspergillus nidulans, Ustilago maydis, Schizosaccharomyces pombe, and Cryptococcus neoformans), in human and mouse, and in plants, suggesting common mechanisms and possible novel drug development targets.