The SAGA Histone Acetyltransferase Complex Regulates Leucine Uptake through the Agp3 Permease in Fission Yeast

Metabolic responses of unicellular organisms are mostly acute, transient, and cell-autonomous. Regulation of nutrient uptake in yeast is one such rapid response. High quality nitrogen sources such as NH4+ inhibit uptake of poor nitrogen sources, such as amino acids. Both transcriptional and posttranscriptional mechanisms operate in nutrient uptake regulation; however, many components of this system remain uncharacterized in the fission yeast, Schizosaccharomyces pombe. Here, we demonstrate that the Spt-Ada-Gcn acetyltransferase (SAGA) complex modulates leucine uptake. Initially, we noticed that a branched-chain amino acid auxotroph exhibits a peculiar adaptive growth phenotype on solid minimal media containing certain nitrogen sources. In fact, the growth of many auxotrophic strains is inhibited by excess NH4Cl, possibly through nitrogen-mediated uptake inhibition of the corresponding nutrients. Surprisingly, DNA microarray analysis revealed that the transcriptional reprogramming during the adaptation of the branched-chain amino acid auxotroph was highly correlated with reprogramming observed in deletions of the SAGA histone acetyltransferase module genes. Deletion of gcn5+ increased leucine uptake in the prototrophic background and rendered the leucine auxotroph resistant to NH4Cl. Deletion of tra1+ caused the opposite phenotypes. The increase in leucine uptake in the gcn5Δ mutant was dependent on an amino acid permease gene, SPCC965.11c+. The closest budding yeast homolog of this permease is a relatively nonspecific amino acid permease AGP3, which functions in poor nutrient conditions. Our analysis identified the regulation of nutrient uptake as a physiological function for the SAGA complex, providing a potential link between cellular metabolism and chromatin regulation. Background: SAGA is a multiprotein complex that possesses histone acetyltransferase activity. Results: Fission yeast strains with deletions in the SAGA acetyltransferase subunit exhibited increased leucine uptake in a manner dependent on an amino acid permease gene. Conclusion: SAGA regulates amino acid uptake in fission yeast. Significance: Regulation of nutrient uptake by SAGA provides a potential link between cellular metabolism and chromatin regulation.