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

Tsang, Felicia; James, Christol; Kato, Michiko; Myers, Victoria; Ilyas, Irtqa; Tsang, Matthew; Lin, Su

doi:10.1074/jbc.m115.644534

Cited by 21 publications

(27 citation statements)

References 66 publications

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“…This screen system was based on our observations that yeast cells release and transport NR back into the cell (19), a phenomenon that is also conserved in human cells (20). Our studies have identified novel NAD + homeostasis factors including the phosphate responsive signaling (PHO) pathway (17), the SPS amino acid sensing pathway (21), a conserved vacuolar NR transporter Fun26 (1,17) and several NAD + metabolic enzymes (22).…”

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confidence: 99%

A functional link between NAD+ homeostasis and N-terminal protein acetylation in Saccharomyces cerevisiae

Croft¹,

Raj²,

Salemi

et al. 2018

Journal of Biological Chemistry

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(Fig. 1D, upper panel).Similar to pnc1∆ mutant (Fig. 1B), both nat3∆and mdm20∆ released mostly NAM not NA (Fig.1D, lower panel). Fig. 1E (Fig. 2E, top panel) had a lesser effect (Fig. 2E, bottom (Fig. 3B). Next, we tested whether deleting ATG14 was sufficient to restore NAD + levels in the NatB mutants. As shown in Fig. 3C (left panel), deleting ATG14did not rescue the low NAD + levels in nat3∆ cells. Similarly, deleting other factors contributing to NR and NAM production ( Fig. 1A and Fig. 2E) in nat3∆ cells also failed to restore the NAD + level back to wild type ( shown to restore actin cable formation in NatB mutants (23,24,28,29). Interestingly, both TPM1-oe and TPM1-5 largely blocked NA/NAM release in the nat3∆ mutant (Fig. 3D) 1A). N-terminal acetyltransferases have specific targets that are largely determined by the sequence of the first two amino acids. NatB acetylates proteins with a MET-retained residue, followed by ASP, GLU, GLN, or ASN as the second residue (25,26,39,40). Nma1 and Nma2 have a MET-ASP N-terminus, but neither protein has been identified as a NatB target.Similar to nat3∆ mutant, nma1∆ cells showed decreased NAD + levels, which could not be rescued by supplementing NR (Fig. 4B). As for the controls, NR efficiently restored the NAD + level in the npt1∆ mutant, which has functional NR salvage (Fig. 4B). The similarities between nma1∆ and nat3∆ mutants suggested that Nma1and Nma2 activities are likely reduced in nat3∆ cells. Since N-terminal acetylation may affect the turnover of target proteins, we first determined whether reduced Nma1/Nma2 activities were due to decreased Nma1/Nma2 protein levels. As shown in Fig. 4C, Nma1 and Nma2 protein levels were indeed decreased in nat3∆ cells (Fig. 4C). In addition to Nma1 and Nma2, NAD + homeostasis factors Bna2, Bna5and Hst1 are also potential NatB targets. Bna2and Bna5 are biosynthesis enzymes in the de novo pathway (Fig. 1A) DISCUSSIONIn this study we characterized NatB complex as a novel NAD + homeostasis factor.Mutants lacking components of the NatB complex, NAT3 and MDM20, produce and release excess amount of NA and NAM. Our studies showed two pathways downstream of NatB contribute to NAD + homeostasis (Fig. 5).In one, NatB is important for proper NAD + biosynthesis by regulating Nma1/Nma2. NatB mutants have low NAD + levels (Fig. 2C), and all NAD + precursors examined failed to restore the NAD + levels ( Fig. 4A and 4B). This suggests that a NAD + biosynthesis factor(s) required for utilization of all NAD + precursors is defected in NatB mutants. Nma1 and Nma2 are such targets because they are the only factors required for all three NAD + biosynthesis pathways (de novo, NA/NAM salvage, and NR salvage) (Fig. 1A), and the N-terminal amino acid sequences are a match for NatB acetylation. In addition, nma1∆and nat3∆ mutants showed similar NAD + utilization defects (Fig. 4B). Although Nma2 is present in both mutants, Nma2 is known to play a minor role in NAD + metabolism. Supporting this model, decreased Nma1 protein level was observed in t...

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confidence: 99%

A functional link between NAD+ homeostasis and N-terminal protein acetylation in Saccharomyces cerevisiae

Croft¹,

Raj²,

Salemi

et al. 2018

Journal of Biological Chemistry

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“…Both sensors also directly activate their transcription factors to induce changes in gene expression targets. Recently in yeast, decreased SPS pathway activity was shown to extend replicative life span (Tsang et al, 2015), which was further increased by CR. SPS-induced life span extension required components of the malate-pyruvate NADH shuttle and partially required Pho8, a vacuolar phosphatase.…”

Section: Amino Acid Sensing Pathwaysmentioning

confidence: 99%

“…SPS-induced life span extension required components of the malate-pyruvate NADH shuttle and partially required Pho8, a vacuolar phosphatase. Decreased SPS activity also increased phosphate sensing ( PHO ) pathway expression, thus active SPS likely has a repressive effect on PHO pathway components (Tsang et al, 2015) (see 5. Phosphate sensing pathway for cross-talk).…”

Section: Amino Acid Sensing Pathwaysmentioning

confidence: 99%

“…Recently, PHO pathway was linked to life span: Pho8, a target of PHO pathway, was partially required for reduced SPS-mediated life span extension (Tsang et al, 2015). In this section we will discuss Pi sensing and response by the PHO pathway and cross-talk with other pathways.…”

Section: Phosphate Sensing Pathwaymentioning

confidence: 99%

“…Also, expression of Pho8, increases under reduced SPS activity, independent of the canonical PHO transcription factors Pho2 and Pho4. Full SPS-mediated life span extension also required Pho8 (Tsang et al, 2015). Thus components of PHO pathway may also be activated under other conditions or sensor pathways.…”

Section: Phosphate Sensing Pathwaymentioning

confidence: 99%

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

Tsang

Lin

2015

Front. Biol.

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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.

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Cellular lifespan and senescence: a complex balance between multiple cellular pathways

2016

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The study of cellular senescence and proliferative lifespan is becoming increasingly important because of the promises of autologous cell therapy, the need for model systems for tissue disease and the implication of senescent cell phenotypes in organismal disease states such as sarcopenia, diabetes and various cancers, among others. Here, we explain the concepts of proliferative cellular lifespan and cellular senescence, and we present factors that have been shown to mediate cellular lifespan positively or negatively. We review much recent literature and present potential molecular mechanisms by which lifespan mediation occurs, drawing from the fields of telomere biology, metabolism, NAD + and sirtuin biology, growth factor signaling and oxygen and antioxidants. We conclude that cellular lifespan and senescence are complex concepts that are governed by multiple independent and interdependent pathways, and that greater understanding of these pathways, their interactions and their convergence upon specific cellular phenotypes may lead to viable therapies for tissue regeneration and treatment of age-related pathologies, which are caused by or exacerbated by senescent cells in vivo.

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

Cited by 21 publications

References 66 publications

A functional link between NAD+ homeostasis and N-terminal protein acetylation in Saccharomyces cerevisiae

A functional link between NAD+ homeostasis and N-terminal protein acetylation in Saccharomyces cerevisiae

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

Cellular lifespan and senescence: a complex balance between multiple cellular pathways

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