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

doi:10.1007/s11515-015-1367-x

Front. Biol.

2015, Vol. 10

Issue (4) : 333-357 https://doi.org/10.1007/s11515-015-1367-x

REVIEW

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

Felicia Tsang,Su-Ju Lin(

)

Department of Microbiology and Molecular Genetics, College of Biological Sciences, University of California, Davis, CA 95616, USA

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Abstract

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.

Keywords nutrient sensing NAD⁺ homeostasis yeast longevity

Corresponding Author(s): Su-Ju Lin

Just Accepted Date: 10 July 2015 Online First Date: 04 August 2015 Issue Date: 14 August 2015

Cite this article:

Felicia Tsang,Su-Ju Lin. Less is more: Nutrient limitation induces cross-talk of nutrient sensing pathways with NAD⁺ homeostasis and contributes to longevity[J]. Front. Biol., 2015, 10(4): 333-357.

URL:

https://academic.hep.com.cn/fib/EN/10.1007/s11515-015-1367-x
https://academic.hep.com.cn/fib/EN/Y2015/V10/I4/333

Fig.1 Nutrient sensing pathways that have been linked to life span in yeast. Amino acids, preferred nitrogen sources, carbon sources and phosphate are sensed by yeast cells through various signaling pathways. Some of these pathways cross-talk via shared targets. Major functions of each pathway are summarized in the sections “PKA and carbon-source sensing pathways” to “Phosphate sensing pathway. ” Abbreviations of the key players shown here are defined in the order of left to right and top to bottom. SPS: Ssy1-Ptr3-Ssy5 amino acid sensing pathway. Yck1/2: yeast casein kinase 1/2. Stp1/2: SPS pathway transcription factors. GAAC: general amino acid control. Gcn2: general control nonderepressible kinase. Gcn4: general control nonderepressible, leucine-zipper transcription factor. TORC2: target of rapamycin complex 2. Ypk1/2: yeast protein kinase; serine/threonine protein kinase. TORC1: target of rapamycin complex 1. Tap42-PP2A: Tap42: two A phosphatase associated protein; PP2A: protein phosphatase 2A; complex. Npr1: nitrogen permease reactivator; kinase. Gln3: glutamine metabolism; TOR transcription factor. Rtg1/3: retrograde response transcription factors. Rim15: serine/threonine kinase. Pkh1/2: PKB-activating kinase homolog 1/2; serine/threonine kinases. Sch9: S6 kinase homolog. Snf3-Rgt2: plasma membrane sensors; Snf3: sucrose non-fermenting; low glucose sensor, Rgt2; restores glucose transport; high glucose sensor. Rgt1: restores glucose transport; glucose-responsive transcription factor. SNF1: sucrose non-fermenting 1; complex. Mig1: multicopy inhibitor of GAL gene expression; transcription repressor. PKA: glucose-sensing cyclic AMP-protein kinase A pathway. Msn2/4: zinc finger STRE (stress response element; AGGGG) binding transcription factors. Pnc1: nicotinamide deamidase. Gis1: zinc finger STRE binding transcription factors. Pho85-Pho80: Pho80: cyclin, Pho85: cyclin dependent kinase; complex. Pho4: PHO pathway transcription factor.

Fig.2 NAD⁺ biosynthetic pathways in S. cerevisiae. NAD⁺ is synthesized from two key intermediates, nicotinic acid mononucleotide (NaMN) and nicotinamide mononucleotide (NMN), via the de novo and NA/Nam/NR salvaging pathways. Trp: tryptophan. QA: quinolinic acid. NaMN: nicotinic acid mononucleotide. NaAD: nicotinic acid adenine dinucleotide. NAD⁺: nicotinamide adenine dinucleotide. Nam: nicotinamide. NA: nicotinic acid. NR: nicotinamide riboside. NMN: nicotinamide mononucleotide. Bna: Bna2, Bna7, Bna1, Bna4, Bna5. Bna6: phosphorybosyltransferase; transfers the phosphoribose moiety of phosphoribosyl pyrophosphate (PRPP). Nma1, Nma2: NaMN and NMN adenylyltransferase, transfers the AMP moiety from ATP. Qns1: a glutamine-dependent NAD⁺ synthetase. Sir2 Family: Sir2, Hst1, Hst2, Hst3, Hst4. Pnc1: deamidase. Npt1: phosphorybosyltransferase. Meu1, Pnp1, Urh1: nucleosidases, can also convert nicotinic acid riboside (NaR) to NA (not shown). Nrk1: NR kinase, can also convert NaR to NaMN (not shown). Pof1: NMN adenylyltransferases. Not shown: Tna1, NA transporter, also imports QA. Nrt1, high-affinity NR transporter. Isn1, Sdt1, nucleotidases, and Pho5, Pho8 phosphatases, which convert NMN to NR.

Fig.3 Nutrient sensing pathways that cross-talk with or cross-regulate the NAD⁺ biosynthetic pathways. NAD⁺ metabolism produces Nam, which is inhibitory to the activity of Sir2 family proteins as NAD⁺-dependent protein deacetylases. Also the Sir2 family, Hst1, can repress de novo NAD⁺ synthesis by silencing the expression of BNA genes. TORC1/Sch9/PKA/Pho85 may inhibit NA/NAM salvage via regulating Pnc1. Reduced SPS pathway activity increases PHO pathway activity and also increases PHO8 expression independent of PHO pathway, both leading to increased NR salvage activity. Thus active SPS pathway likely represses PHO activity. Low levels of phosphate activates PHO pathway, leading to concomitant increases in NR salvage activity via phosphatases, Pho8 and Pho5 (not shown), and nucleotidases Sdt1 and Isn1 (not shown). Whereas active Pho85 may activate or inhibit NR salvage activity. When phosphate is plentiful (and PHO pathway is suppressed), PKA helps degrade Pho84 phosphate transporter. When PHO84 is deleted, PHO pathway is activated and NR salvage activity increases. TORC1: target of rapamycin complex 1. Sch9: S6 kinase homolog. PKA: glucose-sensing cyclic AMP-protein kinase A pathway. Pho85: cyclin dependent kinase. Rim15: serine/threonine kinase. Msn2/4: zinc finger STRE (stress response element; AGGGG) binding transcription factors. Pnc1: nicotinamide deamidase. SPS: Ssy1-Ptr3-Ssy5 amino acid sensing pathway. Stp1/2: SPS pathway transcription factors. Pho2/4: PHO pathway transcription factors. Pho8: vacuolar phosphatase. Sdt1: cytoplasmic nucleotidase. Pho84: plasma membrane phosphate transporter. de novo: pathway of NaMN synthesis from tryptophan. NaMN: nicotinic acid mononucleotide. NaAD: nicotinic acid adenine dinucleotide. NAD⁺: nicotinamide adenine dinucleotide. Nam: nicotinamide. NA: nicotinic acid. NR: nicotinamide riboside. NMN: nicotinamide mononucleotide. Sir2 Family: Sir2, Hst1, Hst2, Hst3, Hst4.

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