氨基酸信号通过抑制SIRT4调控细胞氨脱毒  

Amino Acid Downregulate SIRT4 to Detoxify Ammonia

作　　者：胡颂华 冯雨阳 徐薇 赵世民 HU Songhua;FENG Yuyang;XU Wei;ZHAO Shimin(Institutes of Biomedical Sciences,the Obstetrics&Gynaecology Hospital of Fudan University,Shanghai 200032,China)

机构地区：[1]复旦大学附属妇产科医院/生物医学研究院,上海200032

出　　处：《中国细胞生物学学报》2023年第6期829-834,共6页Chinese Journal of Cell Biology

基　　金：国家重点研发计划重点专项(批准号:2018YFA0801300、2018YFA0800300);国家自然科学基金(批准号:92253305、31821002、32230054、31930062、91857000、92157001)资助的课题。

摘　　要：氨基酸是细胞主要的能源物质之一。然而,氨基酸在代谢过程中产生的氨具有很强的神经毒性,因此其需要在肝脏中被转化成尿素排出体外。已有的研究表明,氨的清除主要是通过尿素循环(又称鸟氨酸循环)来完成的,然而这一代谢通路是如何基于细胞内氨基酸水平的变化来被精确调控目前仍不清楚。该团队发现,线粒体中的SIRT4会作为一个去氨甲酰化酶响应细胞内氨基酸水平的变化来调控氨的清除。机制上,氨基酸代谢产生的氨甲酰磷酸(CP)会通过修饰尿素循环代谢酶(ornithine transcarbamylase,OTC)的307位赖氨酸来激活OTC的酶活,促进氨的清除。当感知到氨基酸不足时,细胞会通过GCN2-Eif2A-ATF4信号通路上调SIRT4的表达,进而去除OTC上的氨甲酰化修饰,关闭尿素循环。针对这一调控机制,该团队发现敲除Sirt4会降低小鼠的血氨水平并且改善四氯化碳诱导的肝性脑病。该研究揭示SIRT4是细胞内氨解毒的一个新的调控因子,且SIRT4有望成为肝性脑病的一个新的干预靶点。Amino acids are one of the major sources of cellular energy,yet ammonia produced from amino acid catabolism has serious neurotoxicity.The urea cycle(ornithine cycle)is the primary metabolic pathway involved in ammonia detoxification,but the processes underlying the regulation of ammonia removal by amino acids remain unclear.SIRT4 acts as a decarbamylase that responds to amino acid sufficiency and regulates ammonia removal.Mechanistically,amino acids-derived CP(carbamoyl phosphate)promotes lysine 307 carbamylation(OTC K307-CP)of OTC(ornithine transcarbamylase),which activates OTC and the urea cycle.SIRT4 expression was transcriptionally upregulated by the amino acid insufficiency-activated GCN2-Eif2A-ATF4 axis,leading to decarbamylation of OTC and inactivation of urea cycle.Based on this mechanism,Sirt4 ablation decreased mouse blood ammonia levels and ameliorated CCl4-induced hepatic encephalopathy phenotypes.This study uncovers a novel role of SIRT4 in ammonia detoxification,which could be harnessed to develop a new strategy to cure hepatic encephalopathy.

关 键 词：SIRT4 氨甲酰化修饰 尿素循环 氨基酸代谢 

分 类 号：Q25[生物学—细胞生物学]