Expression mechanism and function of UDP-glucose pyrophosphorylase in Saccharomycese cerevisiae

Abstract

Ugp1, UDP-glucose pyrophosphorylase (UGPase), plays an important role in carbohydrate metabolism because it provides UDP-glucose (UDP-Glc) which is a pivotal metabolite in several metabolic pathways, including the biosynthesis of carbohydrate storage molecules such as glycogen and trehalose, and the formation of some cell wall components in Saccharomyces cerevisiae. Although many regulators have been expected to be involved in the regulation of UGP1, only Pho85 kinase has been reported to inhibit the UGP1 transcription until now. Here, this study suggests that stress-responsive transcription factors Msn2/4 play a crucial role in regulating the expression of UGP1. First, it is observed that Msn2/4 bind to three stress response elements in the promoter of UGP1 depending on protein kinase A (PKA) activity. Also, the result that several stress conditions induced transcription of UGP1 suggests that the regulation of UGP1 mediated by Msn2/4 is involved in the general stress response. Furthermore, the present study shows that the activity of the phosphate response (PHO) pathway affects Msn2/4-dependent regulation of UGP1, implying a novel link between the PKA and PHO pathway. These findings suggest that signals of the PKA, PHO and stress response pathways converge on and regulate the expression of UGP1 via Msn2/4 in S. cerevisiae. Meanwhile, the expression level of UGP1 is required for the production of storage carbohydrate such as glycogen and trehalose. Because of the specific function of trehalose as a stress protectant, the Ugp1 expression contributes to oxidative stress response and chronological life span (CLS). Interestingly, although it was reported that the PKA pathway regulates carbohydrate metabolism negatively, modulations of Ugp1 level suppressed the typical phenotypes concerning glycogen and trehalose accumulation in the PKA-related gene mutants. Also, PKA-dependent phenotypes in anti-oxidant resistance and CLS were also alleviated via adjustment of Ugp1 level. Taken together, these results suggest that the regulation of UPG1 may influence a variety of biological processes under the PKA pathway through adjustments of various carbohydrate levels. Collectively, this study demonstrates that the regulation of Ugp1 level through Msn2/4 contributes to cellular homeostasis by inducing the glucose partitioning to synthesis of carbohydrates which act as defensive metabolites.