Kang Woo Kyu, Kim Yeong Hyeock, Kang Hyun Ah, Kwon Ki-Sun, Kim Jeong-Yoon
Department of Microbiology and Molecular Biology, College of Bioscience and Biotechnology, Chungnam National University, Daejeon, Republic of Korea.
Department of Life Science, Chung-Ang University, Seoul, Republic of Korea.
Elife. 2015 Sep 2;4:e09709. doi: 10.7554/eLife.09709.
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.
沉默信息调节因子2（Sir2）是一种依赖烟酰胺腺嘌呤二核苷酸（NAD⁺）的蛋白质脱乙酰酶，被认为是一种长寿因子，在饮食限制（DR）介导的寿命延长中发挥重要作用。在本研究中，我们发现Sir2在DR介导的寿命延长中的作用取决于酵母中的环磷酸腺苷-蛋白激酶A（cAMP-PKA）和酪蛋白激酶2（CK2）信号通路。Sir2通过使这些基因启动子区域组蛋白H4的赖氨酸16去乙酰化，部分抑制寿命相关基因的转录，如PMA1（编码一种H⁺-ATP酶）和许多核糖体蛋白基因。这种抑制作用通过Sir2的S473磷酸化得以缓解，而S473磷酸化由活跃的cAMP-PKA和CK2信号通路介导。适度的DR可增加野生型酵母的复制寿命，但对表达Sir2-S473E或S473A等位基因的酵母无效，这表明Sir2对DR介导的寿命延长的影响受到S473磷酸化的负调控。我们的结果揭示了Sir2促进寿命延长的一种机制。
