Reduced Ssy1-Ptr3-Ssy5 (SPS) Signaling Extends Replicative Life Span by Enhancing NAD+ Homeostasis in Saccharomyces cerevisiae

• Published in: The Journal of biological chemistry Vol. 290; no. 20; pp. 12753 - 12764
• Main Authors: Tsang, Felicia, James, Christol, Kato, Michiko, Myers, Victoria, Ilyas, Irtqa, Tsang, Matthew, Lin, Su-Ju
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.05.2015; American Society for Biochemistry and Molecular Biology
• Subjects: Alkaline Phosphatase - genetics; Alkaline Phosphatase - metabolism; Carrier Proteins - genetics; Carrier Proteins - metabolism; cell metabolism; Gene Deletion; Gene Expression Regulation, Fungal - physiology; Homeostasis - physiology; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Malate Dehydrogenase - genetics; Malate Dehydrogenase - metabolism; Membrane Proteins - genetics; Membrane Proteins - metabolism; metabolic regulation; Metabolism; NAD - genetics; NAD - metabolism; NAD biosynthesis; nicotinamide riboside salvage; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Serine Proteases - genetics; Serine Proteases - metabolism; Signal Transduction - physiology; Vacuoles - genetics; Vacuoles - metabolism; yeast genetics; yeast metabolism; nicotinamide riboside salvage; cell metabolism; yeast metabolism; yeast genetics; NAD biosynthesis; metabolic regulation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.644534

Attenuated nutrient signaling extends the life span in yeast and higher eukaryotes; however, the mechanisms are not completely understood. Here we identify the Ssy1-Ptr3-Ssy5 (SPS) amino acid sensing pathway as a novel longevity factor. A null mutation of SSY5 (ssy5Δ) increases replicative life span (RLS) by ∼50%. Our results demonstrate that several NAD+ homeostasis factors play key roles in this life span extension. First, expression of the putative malate-pyruvate NADH shuttle increases in ssy5Δ cells, and deleting components of this shuttle, MAE1 and OAC1, largely abolishes RLS extension. Next, we show that Stp1, a transcription factor of the SPS pathway, directly binds to the promoter of MAE1 and OAC1 to regulate their expression. Additionally, deletion of SSY5 increases nicotinamide riboside (NR) levels and phosphate-responsive (PHO) signaling activity, suggesting that ssy5Δ increases NR salvaging. This increase contributes to NAD+ homeostasis, partially ameliorating the NAD+ deficiency and rescuing the short life span of the npt1Δ mutant. Moreover, we observed that vacuolar phosphatase, Pho8, is partially required for ssy5Δ-mediated NR increase and RLS extension. Together, our studies present evidence that supports SPS signaling is a novel NAD+ homeostasis factor and ssy5Δ-mediated life span extension is likely due to concomitantly increased mitochondrial and vacuolar function. Our findings may contribute to understanding the molecular basis of NAD+ metabolism, cellular life span, and diseases associated with NAD+ deficiency and aging. Signaling pathways regulating NAD+ homeostasis and their complex interplay with cell longevity remain unclear. Attenuated SPS (Ssy1-Ptr3-Ssy5) signaling extends replicative life span, which requires increased nicotinamide riboside salvage and functional NADH shuttle. Enhanced NAD+ homeostasis contributes to SPS-induced cell longevity. Studying SPS signaling as a novel longevity factor helps elucidate the complex regulation of NAD+ homeostasis.