Department of Biosciences, University of Helsinki, Viikinkaari 9, Helsinki 00014, Finland; Institute of Biotechnology, University of Helsinki, Viikinkaari 9, Helsinki 00014, Finland.
Department of Biosciences, University of Helsinki, Viikinkaari 9, Helsinki 00014, Finland; Institute of Biotechnology, University of Helsinki, Viikinkaari 9, Helsinki 00014, Finland.
Curr Biol. 2017 Feb 6;27(3):458-464. doi: 10.1016/j.cub.2016.12.032. Epub 2017 Jan 26.
Nutrient-sensing pathways respond to changes in the levels of macronutrients, such as sugars, lipids, or amino acids, and regulate metabolic pathways to maintain organismal homeostasis [1, 2]. Consequently, nutrient sensing provides animals with the metabolic flexibility necessary for enduring temporal fluctuations in nutrient intake. Recent studies have shown that an animal's ability to survive on a high-sugar diet is determined by sugar-responsive gene regulation [3-8]. It remains to be elucidated whether other levels of metabolic control, such as post-translational regulation of metabolic enzymes, also contribute to organismal sugar tolerance. Furthermore, the sugar-regulated metabolic pathways contributing to sugar tolerance remain insufficiently characterized. Here, we identify Salt-inducible kinase 3 (SIK3), a member of the AMP-activated protein kinase (AMPK)-related kinase family, as a key determinant of Drosophila sugar tolerance. SIK3 allows sugar-feeding animals to increase the reductive capacity of nicotinamide adenine dinucleotide phosphate (NADPH/NADP). NADPH mediates the reduction of the intracellular antioxidant glutathione, which is essential for survival on a high-sugar diet. SIK3 controls NADP reduction by phosphorylating and activating Glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway. SIK3 gene expression is regulated by the sugar-regulated transcription factor complex Mondo-Mlx, which was previously identified as a key determinant of sugar tolerance. SIK3 converges with Mondo-Mlx in sugar-induced activation of G6PD, and simultaneous inhibition of SIK3 and Mondo-Mlx leads to strong synergistic lethality on a sugar-containing diet. In conclusion, SIK3 cooperates with Mondo-Mlx to maintain organismal sugar tolerance through the regulation of NADPH/NADP redox balance.
营养感应途径响应大量营养素（如糖、脂质或氨基酸）水平的变化，并调节代谢途径以维持生物体的内稳态[1,2]。因此，营养感应为动物提供了在营养摄入的时间波动中生存所需的代谢灵活性。最近的研究表明，动物在高糖饮食下的生存能力取决于糖应答基因调控[3-8]。尚不清楚其他代谢控制水平（如代谢酶的翻译后调控）是否也有助于生物体的糖耐受性。此外，有助于糖耐受性的糖调节代谢途径仍未充分表征。在这里，我们确定 Salt-inducible kinase 3（SIK3），一种 AMP 激活的蛋白激酶（AMPK）相关激酶家族的成员，是果蝇糖耐受性的关键决定因素。SIK3 允许糖喂养的动物增加烟酰胺腺嘌呤二核苷酸磷酸（NADPH/NADP）的还原能力。NADPH 介导细胞内抗氧化剂谷胱甘肽的还原，这对于在高糖饮食下生存是必不可少的。SIK3 通过磷酸化和激活葡萄糖-6-磷酸脱氢酶（G6PD）来控制 NADP 的还原，G6PD 是戊糖磷酸途径的限速酶。SIK3 基因表达受糖调节的转录因子复合物 Mondo-Mlx 调控，该复合物先前被鉴定为糖耐受性的关键决定因素。SIK3 与 Mondo-Mlx 在糖诱导的 G6PD 激活中协同作用，同时抑制 SIK3 和 Mondo-Mlx 会导致在含糖饮食上产生强烈的协同致死性。总之，SIK3 通过调节 NADPH/NADP 氧化还原平衡与 Mondo-Mlx 合作维持生物体的糖耐受性。
