Abstract
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.
Highlights
Most non-lysosomal/vacuolar protein degradation is carried out by the proteasome in cytosolic and nuclear compartments of eukaryotic cells
Our previous study [8] indicated that post-diauxic shift (PDS) gene transcription mediated by the Gis1 transcription factor (TF) is coordinately modulated by the functions of the proteasome and TORC1
To find the extent to which the proteasome and TORC1 cooperate with regulate gene transcription, we treated exponentially growing pdr5D cells with the drug vehicle, rapamycin (TORC1 inhibitor), MG132 or both drugs
Summary
Most non-lysosomal/vacuolar protein degradation is carried out by the proteasome in cytosolic and nuclear compartments of eukaryotic cells. Proteasome-mediated degradation, a highly regulated process, can be ubiquitin-dependent or ubiquitinindependent [1,2]. The 26S proteasome and its subcomplexes have been implicated in the regulation of gene transcription through a variety of mechanisms, including transcription factor (TF) processing and chromatin association (recently reviewed in [3,4,5]). In a number of cases, including Gcn, and perhaps Gal and Ino2/4 [11], proteasome-mediated degradation of these TFs is necessary to stimulate transcription. The detailed mechanism is not fully understood, it is proposed that these TFs are marked as ‘spent’ after transcription initiation, trapped with the chromatin and unable to stimulate new rounds of transcription. Proteasome-mediated proteolysis destroys such TFs, resets the promoter and allows ‘fresh’ activators to initiate a new round of transcription [5]
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