Pdc2 coordinates expression of the THI regulon in the yeast Saccharomyces cerevisiae

Abstract

Coordination of gene expression in response to different metabolic signals is crucial for cellular homeostasis. In this work, we addressed the role of Pdc2 in the coordinated control of biosynthesis and demand of an essential metabolic cofactor, thiaminediphosphate (ThDP). The DNA binding protein Pdc2 was initially identified as a regulator of the genes PDC1 and PDC5, which encode isoforms of the glycolytic enzyme pyruvate decarboxylase (Pdc). The Pdc2 has also been implicated as a regulator of genes encoding enzymes in ThDP metabolism. The ThDP is the cofactor of Pdc. Using global and gene-specific expression analysis, we show that Pdc2 is required for the upregulation of all genes controlled by thiamine availability. The Pdc2 seems to act together with Thi2, a known transcriptional regulator of THI genes. The requirement for these two factors differs in a gene-specific manner. While the Thi2, in conjunction with Thi3, seems to control expression of THI genes with respect to thiamine availability, the Pdc2 may link the ThDP demand to carbon source availability. Interestingly, the enzymes Pdc1 and Pdc5 are enriched in the nucleus. Both are known to affect gene expression in an autoregulatory mechanism and expression of both is regulated by glucose and Pdc2, further pointing to a role of Pdc2 in coordinating different metabolic signals. Our analysis helps to further define the THI regulon and hence the spectrum of genes/proteins involved in the ThDP homeostasis. In particular, we identify novel proteins putatively involved in thiamine and/or ThDP transport across the plasma and the mitochondrial membrane. In conclusion, the THI regulon is the most interesting system to study principles of genes expression and metabolic coordination and deserves further attention.