PDF(Pubmed)
Abstract：
O-linked N-acetyl-glucosamine glycosylation (O-GlcNAcylation) of intracellular proteins is a dynamic process broadly implicated in age-related disease, yet it remains uncharacterized whether and how O-GlcNAcylation contributes to the natural aging process. O-GlcNAc transferase (OGT) and the opposing enzyme O-GlcNAcase (OGA) control this nutrient-sensing protein modification in cells. Here, we show that global O-GlcNAc levels are increased in multiple tissues of aged mice. In aged liver, carbamoyl phosphate synthetase 1 (CPS1) is among the most heavily O-GlcNAcylated proteins. CPS1 O-GlcNAcylation is reversed by calorie restriction and is sensitive to genetic and pharmacological manipulations of the O-GlcNAc pathway. High glucose stimulates CPS1 O-GlcNAcylation and inhibits CPS1 activity. Liver-specific deletion of OGT potentiates CPS1 activity and renders CPS1 irresponsive to further stimulation by a prolonged fasting. Our results identify CPS1 O-GlcNAcylation as a key nutrient-sensing regulatory step in the urea cycle during aging and dietary restriction, implying a role for mitochondrial O-GlcNAcylation in nutritional regulation of longevity.
摘要：
细胞内蛋白质的O-联N-乙酰-葡糖胺糖基化（O-GlcNAcylation）是一个动态过程，广泛涉及与年龄相关的疾病，然而，它仍然没有表征O-GlcNAcylation是否以及如何有助于自然老化过程。O-GlcNAc转移酶（OGT）和相反的酶O-GlcNAcase（OGA）控制细胞中的这种营养感应蛋白修饰。这里,我们表明，全球O-GlcNAc水平在老年小鼠的多个组织中增加。在老年肝脏中，氨基甲酰磷酸合成酶1（CPS1）是最严重的O-GlcNAcylated蛋白之一。CPS1O-GlcNAcylation被热量限制逆转，对O-GlcNAc途径的遗传和药理操作敏感。高葡萄糖刺激CPS1O-GlcNAcylation并抑制CPS1活性。OGT的肝脏特异性缺失可增强CPS1的活性，并使CPS1对长时间禁食的进一步刺激无反应。我们的结果确定CPS1O-GlcNAcylation是衰老和饮食限制期间尿素循环中关键的营养感知调节步骤，暗示线粒体O-GlcNAcylation在长寿的营养调节中的作用。
