Sir2 phosphorylation through cAMP-PKA and CK2 signaling inhibits the lifespan extension activity of Sir2 in yeast.

Woo Kyu Kang,Hyun Ah Kang,Yeong Hyeock Kim,Ki-Sun Kwon,Jeong-Yoon Kim

doi:10.7554/elife.09709

Abstract

Silent information regulator 2 (Sir2), an NAD(+)-dependent protein deacetylase, has been proposed to be a longevity factor that plays important roles in dietary restriction (DR)-mediated lifespan extension. In this study, we show that the Sir2's role for DR-mediated lifespan extension depends on cAMP-PKA and casein kinase 2 (CK2) signaling in yeast. Sir2 partially represses the transcription of lifespan-associated genes, such as PMA1 (encoding an H(+)-ATPase) and many ribosomal protein genes, through deacetylation of Lys 16 of histone H4 in the promoter regions of these genes. This repression is relieved by Sir2 S473 phosphorylation, which is mediated by active cAMP-PKA and CK2 signaling. Moderate DR increases the replicative lifespan of wild-type yeast but has no effect on that of yeast expressing the Sir2-S473E or S473A allele, suggesting that the effect of Sir2 on DR-mediated lifespan extension is negatively regulated by S473 phosphorylation. Our results demonstrate a mechanism by which Sir2 contributes to lifespan extension.

Highlights

Sirtuins, a highly conserved family of nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylases, have been implicated as a key metabolic sensor to link dietary restriction (DR) with lifespan extension in yeast, worms, flies, and mice (Longo and Kennedy, 2006)
We demonstrate that the phosphorylation of Silent information regulator 2 (Sir2) at S473, which is regulated through cyclic AMP (cAMP)-protein kinase A (PKA) and casein kinase 2 (CK2) signaling, determines the role of Sir2 in replicative lifespan (RLS)
Since DR is known to reduce cAMP-PKA activity (Lin et al, 2000) and both PMA1 and ribosomal protein genes (RPGs) are critical regulators of yeast RLS (Steffen et al, 2008; Ito et al, 2010; Henderson et al, 2014), we investigated the relevance of Sir2 S473 phosphorylation in the DR-mediated lifespan extension

Summary

Introduction

A highly conserved family of nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylases, have been implicated as a key metabolic sensor to link dietary restriction (DR) with lifespan extension in yeast, worms, flies, and mice (Longo and Kennedy, 2006). Silent information regulator 2 (Sir2), the founding member of the sirtuin family, mediates transcriptional silencing at the ribosomal DNA (rDNA) locus, mating type loci and telomeres by deacetylating the acetylated lysine 16 of histone H4 (Rine and Herskowitz, 1987; Hecht et al, 1996; Smith and Boeke, 1997; Imai et al, 2000). Sir may regulate lifespan by deacetylating H4K16 at sub-telomeric regions (Dang et al, 2009) and by asymmetrically segregating damaged proteins and cellular organelles between mother and daughter cells (Aguilaniu et al, 2003; Erjavec and Nystrom, 2007; McFaline-Figueroa et al, 2011). In worms and flies, the role of Sir in lifespan extension is still controversial

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Conclusion