Activation of protein kinase C-mitogen-activated protein kinase signaling in response to inositol starvation triggers Sir2p-dependent telomeric silencing in yeast.
Depriving wild type yeast of inositol, a soluble precursor for phospholipid, phosphoinositide, and complex sphingolipid synthesis, activates the protein kinase C (PKC)-MAPK signaling pathway, which plays a key role in the activation of NAD(+)-dependent telomeric silencing. We now report that triggering PKC-MAPK signaling by inositol deprivation or by blocking inositol-containing sphingolipid synthesis with aureobasidin A results in increased telomeric silencing regulated by the MAPK, Slt2p, and the NAD(+)-dependent deacetylase, Sir2p. Consistent with the dependence on NAD(+) in Sir2p-regulated silencing, we found that inositol depletion induces the expression of BNA2, which is required for the de novo synthesis of NAD(+). Moreover, telomeric silencing is greatly reduced in bna2Δ and npt1Δ mutants, which are defective in de novo and salvage pathways for NAD(+) synthesis, respectively. Surprisingly, however, omitting nicotinic acid from the growth medium, which reduces cellular NAD(+) levels, leads to increased telomeric silencing in the absence of inositol and/or at high temperature. This increase in telomeric silencing in response to inositol starvation is correlated to chronological life span extension but is Sir2p-independent. We conclude that activation of the PKC-MAPK signaling by interruption of inositol sphingolipid synthesis leads to increased Sir2p-dependent silencing and is dependent upon the de novo and salvage pathways for NAD(+) synthesis but is not correlated with cellular NAD(+) levels.
From the Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853.
Sojin
S
Lee
Maria L
ML
Gaspar
Manuel A
MA
Aregullin
Stephen A
SA
Jesch
Susan A
SA
Henry
D004789:Enzyme Activation; D015966:Gene Expression Regulation, Fungal; D020868:Gene Silencing; D017930:Genes, Reporter; D007294:Inositol / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D009154:Mutation; D011493:Protein Kinase C / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000378:metabolism; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae / Q000378:metabolism*; D056565:Sirtuin 2 / Q000378:metabolism*; D013107:Sphingolipids / Q000378:metabolism; D016615:Telomere / Q000648:ultrastructure*; D013696:Temperature
D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; D013107:Sphingolipids; D007294:Inositol; D011493:Protein Kinase C; C087778:SIR2 protein, S cerevisiae; D056565:Sirtuin 2
Inositol Phospholipid; NAD Biosynthesis; Protein Kinase C (PKC); Sirtuins; Sphingolipid