Life span extension and neuronal cell protection by Drosophila nicotinamidase
Life span extension and neuronal cell protection by Drosophila nicotinamidase
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DOI：
10.1074/jbc.m804681200
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发表时间：
2008-10-10
影响因子：
4.8
通讯作者：
Tzivion, Guri
中科院分区：
文献类型：
--
作者：
Balan, Vitaly;Miller, Gregory S.;Tzivion, Guri
模式生物的寿命可以通过影响细胞代谢、氧化或DNA完整性的环境条件来调节。酵母烟酰胺酶基因pnc1被确定为热量限制和应激诱导的寿命延长的关键转录靶点和媒介。PNC1被认为通过调节细胞烟酰胺和NAD水平来影响酵母的寿命，导致Sir2家族III类组蛋白去乙酰化酶的活性增加。在秀丽隐杆线虫（Caenorhabditis elegans）中，pnc1同源物的敲低最近被证明可以缩短蠕虫的寿命，而其过表达可以增加氧化应激条件下的存活。在高等生物中，烟酰胺酶的功能和调控尚未确定。在这里，我们报道了果蝇烟酰胺酶D-NAAM的鉴定和生化特性，并证明其过表达可显着增加果蝇的中位和最大寿命。Sir2突变果蝇的寿命延长是相反的，这表明Sir2依赖性。在果蝇S2细胞中测试D-NAAM的生理效应，我们发现氧化应激在转录水平和蛋白质活性上都是主要的调节因子。与酵母模型相反，应激因素，如高渗透压和热休克、卡路里限制或TOR和磷脂酰肌醇3-激酶途径的抑制剂，似乎不调节S2细胞中的D-NAAM。有趣的是，人类神经元细胞中D-NAAM的表达以sirtin依赖的方式保护氧化应激诱导的细胞死亡。总之，我们的发现建立了延长果蝇烟碱酰胺酶能力的寿命，并提供了烟碱中调节基因在影响寿命和神经元细胞存活的氧化应激调节途径中的作用。
The life span of model organisms can be modulated by environmental conditions that influence cellular metabolism, oxidation, or DNA integrity. The yeast nicotinamidase gene pnc1 was identified as a key transcriptional target and mediator of calorie restriction and stress-induced life span extension. PNC1 is thought to exert its effect on yeast life span by modulating cellular nicotinamide and NAD levels, resulting in increased activity of Sir2 family class III histone deacetylases. In Caenorhabditis elegans, knockdown of a pnc1 homolog was shown recently to shorten the worm life span, whereas its overexpression increased survival under conditions of oxidative stress. The function and regulation of nicotinamidases in higher organisms has not been determined. Here, we report the identification and biochemical characterization of the Drosophila nicotinamidase, D-NAAM, and demonstrate that its overexpression significantly increases median and maximal fly life span. The life span extension was reversed in Sir2 mutant flies, suggesting Sir2 dependence. Testing for physiological effectors of D-NAAM in Drosophila S2 cells, we identified oxidative stress as a primary regulator, both at the transcription level and protein activity. In contrast to the yeast model, stress factors such as high osmolarity and heat shock, calorie restriction, or inhibitors of TOR and phosphatidylinositol 3-kinase pathways do not appear to regulate D-NAAM in S2 cells. Interestingly, the expression of D-NAAM in human neuronal cells conferred protection from oxidative stress-induced cell death in a sirtuin-dependent manner. Together, our findings establish a life span extending the ability of nicotinamidase in flies and offer a role for nicotina-mide-modulating genes in oxidative stress regulated pathways influencing longevity and neuronal cell survival.