Synergistic effects of TOR and proteasome pathways on the yeast transcriptome and cell growth.

The proteasome has been implicated in gene transcription through a variety of mechanisms. How the proteasome regulates genome-wide transcription in relation to nutrient signalling pathways is largely unknown. Using chemical inhibitors to compromise the functions of the proteasome and/or TORC1, we reveal that the proteasome and TORC1 synergistically promote the expression of de novo purine and amino acid biosynthetic genes, and restrict the transcription of those associated with proteolysis, starvation and stress responses. Genetic analysis demonstrates that TORC1 negatively regulates both the Yak1 and Rim15 kinases to modulate starvation-specific gene expression mediated by the Msn2/4 and Gis1 transcription factors. Compromising proteasome function induces starvation-specific gene transcription in exponential-phase cells and abrogates the strict control of such expression by Yak1 and Rim15 in rapamycin-treated cells, confirming that the proteasome functions to ensure stringent control of the starvation response by the TOR pathway. Synergy between the two pathways is also exhibited on cell growth control. Rpn4-dependent upregulation of proteasomal genes and a catalytically competent 20S proteasome are essential for yeast cells to respond to reduced TORC1 activity. These data suggest that the proteasome and the TOR signalling pathway synergistically regulate a significant portion of the genome to coordinate cell growth and starvation response.