title: Reduced Ssy1-Ptr3-Ssy5 (SPS) signaling extends replicative life span by enhancing NAD+ homeostasis in Saccharomyces cerevisiae.
abstract: 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.
authors.affiliation: From the Department of Microbiology and Molecular Genetics, College of Biological Sciences, University of California, Davis, California 95616.
authors.forename: Felicia
authors.initials: F
authors.lastname: Tsang
authors.affiliation: From the Department of Microbiology and Molecular Genetics, College of Biological Sciences, University of California, Davis, California 95616.
authors.forename: Christol
authors.initials: C
authors.lastname: James
authors.affiliation: From the Department of Microbiology and Molecular Genetics, College of Biological Sciences, University of California, Davis, California 95616.
authors.forename: Michiko
authors.initials: M
authors.lastname: Kato
authors.affiliation: From the Department of Microbiology and Molecular Genetics, College of Biological Sciences, University of California, Davis, California 95616.
authors.forename: Victoria
authors.initials: V
authors.lastname: Myers
authors.affiliation: From the Department of Microbiology and Molecular Genetics, College of Biological Sciences, University of California, Davis, California 95616.
authors.forename: Irtqa
authors.initials: I
authors.lastname: Ilyas
authors.affiliation: From the Department of Microbiology and Molecular Genetics, College of Biological Sciences, University of California, Davis, California 95616.
authors.forename: Matthew
authors.initials: M
authors.lastname: Tsang
authors.affiliation: From the Department of Microbiology and Molecular Genetics, College of Biological Sciences, University of California, Davis, California 95616 slin@ucdavis.edu.
authors.forename: Su-Ju
authors.initials: SJ
authors.lastname: Lin
mesh_terms: D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D015966:Gene Expression Regulation, Fungal / Q000502:physiology; D006706:Homeostasis / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008291:Malate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009243:NAD / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D057057:Serine Proteases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014617:Vacuoles / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C106976:PTR3 protein, S cerevisiae; C120527:SSY1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D009243:NAD; C112602:MAE1 protein, S cerevisiae; D008291:Malate Dehydrogenase; D000469:Alkaline Phosphatase; C510355:PHO8 protein, S cerevisiae; D057057:Serine Proteases; C550846:Ssy5 protein, S cerevisiae
keywords: NAD biosynthesis; cell metabolism; metabolic regulation; nicotinamide riboside salvage; yeast genetics; yeast metabolism
references.citation: Genetics. 2012 Sep;192(1):73-105
references.pmid: 22964838
references.citation: Methods Mol Biol. 2011;780:191-208
references.pmid: 21870262
references.citation: Eukaryot Cell. 2013 May;12(5):648-53
references.pmid: 23457190
references.citation: Mol Cell. 2014 Jul 17;55(2):253-63
references.pmid: 24882210
references.citation: Trends Cell Biol. 2014 Aug;24(8):464-71
references.pmid: 24786309
references.citation: J Biol Chem. 2014 May 30;289(22):15577-87
references.pmid: 24759102
references.citation: Science. 2014 Nov 7;346(6210):751-5
references.pmid: 25236469
references.citation: Mol Biol Cell. 2014 Nov 15;25(23):3823-33
references.pmid: 25253722
references.citation: DNA Repair (Amst). 2014 Nov;23:49-58
references.pmid: 25096760
references.citation: Nucleic Acids Res. 2000 Feb 15;28(4):974-81
references.pmid: 10648791
references.citation: FEMS Microbiol Rev. 2001 Jan;25(1):15-37
references.pmid: 11152939
references.citation: Science. 2001 Apr 13;292(5515):288-90
references.pmid: 11292860
references.citation: Genetics. 2001 Jul;158(3):973-88
references.pmid: 11454748
references.citation: Mol Microbiol. 2001 Oct;42(1):215-28
references.pmid: 11679080
references.citation: Genetics. 2001 Dec;159(4):1491-9
references.pmid: 11779791
references.citation: Curr Genet. 2002 May;41(2):63-72
references.pmid: 12073087
references.citation: Nature. 2002 Jul 25;418(6896):387-91
references.pmid: 12140549
references.citation: Mol Microbiol. 2002 Dec;46(5):1319-33
references.pmid: 12453218
references.citation: Genes Dev. 2004 Jan 1;18(1):12-6
references.pmid: 14724176
references.citation: Genetics. 2004 Apr;166(4):1727-39
references.pmid: 15126393
references.citation: Cell. 2004 May 14;117(4):495-502
references.pmid: 15137942
references.citation: Yeast. 2004 Jun;21(8):635-48
references.pmid: 15197729
references.citation: Mol Cell Biol. 1985 Jan;5(1):248-52
references.pmid: 2984552
references.citation: Biochim Biophys Acta. 1995 Nov 30;1269(3):275-80
references.pmid: 7495881
references.citation: Nucleic Acids Res. 1996 Jul 1;24(13):2519-24
references.pmid: 8692690
references.citation: Trends Biochem Sci. 1996 Oct;21(10):383-7
references.pmid: 8918192
references.citation: Yeast. 1998 Jan 30;14(2):115-32
references.pmid: 9483801
references.citation: J Bacteriol. 1998 May;180(9):2556-9
references.pmid: 9573211
references.citation: Science. 1999 Feb 12;283(5404):981-5
references.pmid: 9974390
references.citation: Mol Cell Biol. 1999 Aug;19(8):5405-16
references.pmid: 10409731
references.citation: Genome Res. 2005 Aug;15(8):1145-52
references.pmid: 16077013
references.citation: Science. 2005 Nov 18;310(5751):1193-6
references.pmid: 16293764
references.citation: Genes Dev. 2006 Jan 15;20(2):174-84
references.pmid: 16418483
references.citation: Genes Dev. 2006 Jun 15;20(12):1563-8
references.pmid: 16778074
references.citation: Cell. 2006 Sep 8;126(5):941-54
references.pmid: 16959573
references.citation: J Biol Chem. 2007 Jan 5;282(1):594-605
references.pmid: 17085444
references.citation: J Biol Chem. 2007 Mar 2;282(9):6161-71
references.pmid: 17200108
references.citation: Cell. 2007 May 4;129(3):473-84
references.pmid: 17482543
references.citation: PLoS Biol. 2007 Oct 2;5(10):e263
references.pmid: 17914902
references.citation: Mol Cell Biol. 2008 Jan;28(2):551-63
references.pmid: 17984223
references.citation: Genes Dev. 2008 Apr 1;22(7):931-44
references.pmid: 18381895
references.citation: Mol Ecol. 2008 Jun;17(12):2985-97
references.pmid: 18422925
references.citation: Annu Rev Nutr. 2008;28:115-30
references.pmid: 18429699
references.citation: Xenobiotica. 2008 Jul;38(7-8):995-1021
references.pmid: 18668437
references.citation: Biochem Soc Trans. 2009 Feb;37(Pt 1):242-7
references.pmid: 19143640
references.citation: Methods Enzymol. 2008;451:33-42
references.pmid: 19185711
references.citation: J Biol Chem. 2009 Jun 19;284(25):17110-9
references.pmid: 19416965
references.citation: Curr Genet. 1999 Dec;36(6):317-28
references.pmid: 10654085
references.citation: Science. 2000 Sep 22;289(5487):2126-8
references.pmid: 11000115
references.citation: Mol Cell Biol. 2001 Feb;21(3):814-26
references.pmid: 11154269
references.citation: Genetics. 2012 Mar;190(3):885-929
references.pmid: 22419079
references.citation: Genome Biol. 2011;12(12):R125
references.pmid: 22189060
references.citation: Science. 2012 Jul 6;337(6090):96-100
references.pmid: 22628558
references.citation: Genes Dev. 2009 Jun 15;23(12):1399-407
references.pmid: 19528318
references.citation: J Biol Chem. 2009 Dec 11;284(50):34861-9
references.pmid: 19846558
references.citation: Genetics. 2009 Dec;183(4):1373-84
references.pmid: 19805817
references.citation: J Biol Chem. 2010 Jan 8;285(2):855-65
references.pmid: 19906648
references.citation: Mol Cell Biol. 2010 Jul;30(13):3329-41
references.pmid: 20439498
references.citation: J Biol Chem. 2011 Feb 11;286(6):4620-31
references.pmid: 21127045
references.citation: J Biol Chem. 2011 Apr 8;286(14):12006-15
references.pmid: 21310956
references.citation: J Biol Chem. 2011 Apr 22;286(16):14271-81
references.pmid: 21349851
references.citation: Mol Biol Cell. 2011 Aug 1;22(15):2754-65
references.pmid: 21653827
references.citation: Nature. 2012 Dec 13;492(7428):261-5
references.pmid: 23172144