Functional dissection of the glucose signaling pathways that regulate the yeast glucose transporter gene (HXT) repressor Rgt1

The yeast Rgt1 repressor is a bifunctional protein that acts as a transcriptional repressor and activator. Under glucose-limited conditions, Rgt1 induces transcriptional repression by forming a repressive complex with its corepressors Mth1 and Std1. Here, we show that Rgt1 is converted from a transcriptional repressor into an activator under high glucose conditions and this occurs through two independent but consecutive events mediated by two glucose signaling pathways: (1) disruption of the repressive complex by the Rgt2/Snf3 pathway; (2) phosphorylation of Rgt1 by the cAMP-PKA (cAMP-dependent protein kinase) pathway. Rgt1 is phosphorylated by PKA at four serine residues within its amino-terminal region, but this does not occur until the repressive complex is disrupted. While phosphorylation of any one of these sites is sufficient to enable Rgt1 to induce transcriptional activation, phosphorylation of all the sites results in the release of Rgt1 from DNA. We discuss how the bifunctional properties of Rgt1 are regulated through differential phosphorylation

Less is more: Nutrient limitation induces cross-talk of nutrient sensing pathways with NAD+ homeostasis and contributes to longevity

Nutrient sensing pathways and their regulation grant cells control over their metabolism and growth in response to changing nutrients. Factors that regulate nutrient sensing can also modulate longevity. Reduced activity of nutrient sensing pathways such as glucose-sensing PKA, nitrogen-sensing TOR and S6 kinase homolog Sch9 have been linked to increased life span in the yeast, Saccharomyces cerevisiae, and higher eukaryotes. Recently, reduced activity of amino acid sensing SPS pathway was also shown to increase yeast life span. Life span extension by reduced SPS activity requires enhanced NAD(+) (nicotinamide adenine dinucleotide, oxidized form) and nicotinamide riboside (NR, a NAD(+) precursor) homeostasis. Maintaining adequate NAD(+) pools has been shown to play key roles in life span extension, but factors regulating NAD(+) metabolism and homeostasis are not completely understood. Recently, NAD(+) metabolism was also linked to the phosphate (Pi)-sensing PHO pathway in yeast. Canonical PHO activation requires Pi-starvation. Interestingly, NAD(+) depletion without Pi-starvation was sufficient to induce PHO activation, increasing NR production and mobilization. Moreover, SPS signaling appears to function in parallel with PHO signaling components to regulate NR/NAD(+) homeostasis. These studies suggest that NAD(+) metabolism is likely controlled by and/or coordinated with multiple nutrient sensing pathways. Indeed, cross-regulation of PHO, PKA, TOR and Sch9 pathways was reported to potentially affect NAD(+) metabolism; though detailed mechanisms remain unclear. This review discusses yeast longevity-related nutrient sensing pathways and possible mechanisms of life span extension, regulation of NAD(+) homeostasis, and cross-talk among nutrient sensing pathways and NAD(+) homeostasis