Regulation of Gene Expression by Amino Acids in Animal Cells
Regulation of Gene Expression by Amino Acids in Animal Cells
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DOI：
10.1007/978-3-030-74180-8_1
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发表时间：
2021-01-01
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影响因子：
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通讯作者：
Bazer, Fuller W.
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文献类型：
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作者：
Sah, Nirvay;Wu, Guoyao;Bazer, Fuller W.
氨基酸在动物生物学中具有多种作用，包括蛋白质和葡萄糖的合成、细胞代谢、抗氧化反应、免疫增强剂以及基因表达的诱导或抑制剂。近年来的研究揭示了氨基酸在动物基因表达调控中的重要作用。细胞氨基酸传感器及其机制途径的发现扩大了我们对身体如何对营养物质特别是氨基酸的剥夺作出反应的理解。细胞外氨基酸浓度的改变可以调节基因和蛋白质的转录、翻译、转录后修饰和表观遗传调控。细胞内具有氨基酸传感器，如针对亮氨酸的Sestrin2和针对精氨酸的CASTOR2，它们分别对氨基酸的充足或缺乏作出反应，从而抑制或激活下游基因表达信号。细胞中氨基酸的充足性确保其与同源传感器结合并抑制MTOR抑制剂，从而增加全球蛋白质合成。另一方面，氨基酸的剥夺激活了氨基酸反应通路（GCN2-eIF2a-ATF4），导致活化转录因子4 （ATF4）的选择性翻译增加。氨基酸本身缺乏或通过ATF4抑制MTORC1活性的作用限制了整体蛋白质合成。ATF4对低浓度的细胞氨基酸作出反应，介导氨基酸转运和生物合成（ASNS、CAT-1、SNAT2）、自噬（ATG3、ATG10、ATG12）和丝氨酸-甘氨酸合成（PHGDH、PSAT1、PSPH、MTHFD2）等基因群的转录。长期氨基酸饥饿对细胞有显著影响：抑制正常细胞生长和代谢所需基因的表达和翻译，增强细胞适应和生存所需基因的表达。氨基酸水平也通过乙酰化、adp核糖基化、二硫键形成、谷氨酰化和羟基化等机制影响蛋白质的翻译后修饰。
Amino acids have pleiotropic roles in animal biology including protein and glucose synthesis, cellular metabolism, antioxidant reactions, immune enhancers, and inducers or suppressors of gene expression. Recent studies have revealed important roles of amino acids in the regulation of gene expression in animals. Discoveries of cellular amino acid sensors and their mechanistic pathways have broadened our understanding of how the body responds to the deprivation of nutrients and amino acids in particular. Alterations in concentrations of extracellular amino acids can modulate transcription, translation, posttran-scriptional modifications, and epigenetic regulation of genes and proteins. Cells have intracellular amino acid sensors, for example, Sestrin2 for leucine and CASTOR2 for arginine, that respond to sufficiency or deficiency in amino acids, thereby inhibiting or activating downstream signals for gene expression, respectively. The sufficiency of an amino acid in cells ensures its binding to cognate sensors and suppression of inhibitors of MTOR, leading to increased global protein synthesis. On the other hand, deprivation of amino acids activates the amino acid response pathway (GCN2-eIF2a-ATF4), leading to increased selective translation of the activating transcription factor 4 (ATF4). Deficiency of an amino acid itself or via the action of ATF4 suppression of MTORC1 activity limits global protein synthesis. ATF4, in response to low concentrations of cellular amino acids, mediates the transcription of groups of genes such as those for amino acid transport and biosynthesis (ASNS, CAT-1, SNAT2), autophagy ( ATG3, ATG10, ATG12), and serine-glycine synthesis (PHGDH, PSAT1, PSPH, MTHFD2). Long-term amino acid starvation has a pronounced effect on cells: suppressed expression and translation of genes required for normal cell growth and metabolism and enhanced expression of genes required for cell adaptation and survival. Levels of amino acids also affect the posttranslational modifications of proteins through mechanisms such as acetylation, ADP-ribosylation, disulfide bond formation, glutamylation, and hydroxylation.