Salmonella enterica中心代谢关键酶的赖氨酸可逆乙酰化修饰研究
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摘要
蛋白质翻译后修饰是表观遗传学的重要内容,赖氨酸可逆乙酰化修饰由于同组蛋白修饰、热量限制、细胞凋亡、寿命延长和转录沉默等生理过程密切相关逐渐成为人们研究的热点。近年来,有关真核生物的乙酰化调控研究成果日新月异,而原核生物的乙酰化调控研究由于手段的缺乏和基础的薄弱几乎是处于停滞不前的状态。
本论文利用赖氨酸乙酰化抗体的特异性,结合免疫沉淀和质谱技术的高效分离特性,首次对原核生物Salmonella enterica的乙酰化底物蛋白进行了蛋白组学水平的扫描,揭示乙酰化修饰与各种代谢关系密切；以可发酵碳源葡萄糖和不可发酵碳源柠檬酸为碳源,研究乙酰化修饰与不同代谢途径之间的关系,并且从表型、生化和遗传三个水平深入研究了乙酰化修饰对S. enterica中心代谢的调控机制,首次揭示赖氨酸可逆乙酰化修饰是中心代谢在整体水平上的一种调控方式；同时结合我们合作实验室关于真核生物乙酰化修饰的研究结果,提出赖氨酸可逆乙酰化修饰是一种广泛存在于真核和原核生物中的非常保守的中心代谢的调控机制。
整个研究分为以下四个部分展开。
第一部分我们利用免疫沉淀的高灵敏性富集赖氨酸乙酰化肽段,并利用质谱技术的高分辨率,首次对原核生物S. enterica的赖氨酸乙酰化修饰底物蛋白在蛋白组学水平上进行了扫描研究,得到一系列与能量代谢、转录调控、氨基酸和核酸合成等密切相关的乙酰化修饰底物蛋白。本试验结果发现有166个蛋白的190个肽段是乙酰化的,且其中的77个蛋白是与代谢相关的,这大大超出了我们对乙酰化修饰的预期,为原核生物的乙酰化研究开辟了一个新的天地。
第二部分我们采用Red重组技术成功获得了S. enterica的乙酰基转移酶(Pat)和/或去乙酰化酶(CobB)缺失的突变株,并对它们在葡萄糖和柠檬酸为唯一碳源的基本培养基上的生长表型进行了研究,结果发现S. enterica及其衍生菌株在不同碳源基本培养基中展示出截然不同的生长表型,确认了乙酰化修饰与S. enterica能量代谢之间的密切关系,并提出乙酰基转移酶(Pat)和去乙酰化酶(CobB)可能是目前唯一已知的能够对S. enterica中心代谢关键酶起可逆乙酰化修饰调控的乙酰化修饰酶。
第三部分我们克隆并表达了乙酰基转移酶(Pat)和去乙酰化酶(CobB)以及中心代谢关键酶,如3-磷酸甘油醛脱氢酶(GapA)、异柠檬酸脱氢酶激酶/磷酸化酶(AceK)和异柠檬酸裂解酶(AceA),并在体外重构Pat/CobB介导的乙酰化/去乙酰化修饰体系,研究乙酰化修饰对这些酶活性的调控方式；同时构建GapA、AceK和AceA乙酰化修饰位点的点突变蛋白和敲除突变株,体外测定酶活力变化,研究这三个酶的具体乙酰化修饰位点,并进行表型互补试验。结果发现GapA的脱氢酶活力与乙酰化修饰正相关,而AceK的激酶活力和AceA裂解酶活力与乙酰化修饰负相关,且GapA的第108、115、321和331位赖氨酸,AceK的第72、83和553位赖氨酸,AceA的第13和308位赖氨酸与乙酰化修饰密切相关。
第四部分我们以核糖体RNA 16S rRNA为内参基因,利用定量荧光实时PCR研究乙酰基转移酶(Pat)和去乙酰化酶(CobB)的转录与不同代谢途径乙酰化修饰之间的关系,结果显示：在葡萄糖为碳源的情况下,pat和cobB的转录水平要高于柠檬酸为碳源；不管是葡萄糖还是以柠檬酸为碳源,对数期pat和cobB的转录水平均要高于它们在稳定期和迟滞期的转录水平；提出存在一个乙酰化潜能(pat mRNA/cobB mRNA)的概念,即pat和cobB的转录水平决定了不同时期的乙酰化修饰水平。通过qRT-PCR试验,在转录水平验证了乙酰化修饰与不同碳源代谢之间的相互关系。
综上所述,本论文综合乙酰化修饰在生理、生化和遗传三个方面的证据,验证了乙酰化修饰是一种广泛存在于原核生物S. enterica中的调控方式；提出S.enterica不同代谢通路转换的分子机制是通过乙酰基转移酶(Pat)和去乙酰化酶(CobB)的共同作用,对中心代谢关键酶类如GapA, AceA和AceK等进行可逆的乙酰化修饰,从整体水平上调控中心代谢；结合我们合作伙伴在真核生物中的研究结果,我们认为代谢关键酶类赖氨酸残基的可逆乙酰化修饰不管是在原核生物还是在真核生物中,在进化上都是一种非常保守的调控机制。
以上结果为原核生物的乙酰化修饰研究开辟了一个新的领域。
Protein post-translation modification is an important content of epigenetics. The pivotal importance of lysine-acetylation and its regulatory enzymes to the several fundamental cellular processes in mammalian cells, including histone modification, calorie restriction, cell apoptosis, life span extension, transcription silencing and so on, continues to be revealed at a remarkable pace. Recently, the study of lysine-acetylation in eukaryote changes with each passing day, and while the extent and function of this modification in prokaryotic remain largely unexplored because of the absence of research means and weak basis, thereby presenting a hurdle to further functional study of this modification in prokaryotic systems.
Here we reported the first global scanning of lysine-acetylation in the prokaryote S. enterica by efficient affinity enrichment of lysine acetylated peptide with homemade lysine-acetylation antibody, combining with the high resolving power of immunoprecipitation and mass spectrum, and subsequently do the further study of these acetylation substrate enzymes of S. enterica central metabolism and energy metabolism from the physiological, biochemical, and genetic levels. Integrating with our collaborator's eukaryote results, we propose that reversible lysine acetylation of metabolic enzymes is the mechanism of global regulation of the central metabolism circuits and represents an evolutionarily conserved universal mechanism in metabolic regulation in both eukaryote and prokaryotes.
Our study includes four parts.
In the first part, we firstly applied the high sensitivity of immunoprecipitation to enrich the lysine acetylated peptides and did the proteomics screening of lysine-acetylation substrate proteins in S. enterica, whereafter used the high resolution of HPLC/mass spectrometer to identify acetylated peptides. The screening identified a series of acetylated substrate proteins correlated with energy metabolism, transcription modulation, amino acid and nucleic acid biosynthesis and so on. We discover that 190 modification sites in 166 proteins from S. enterica are acetylated, of which 77 proteins are correlated with metabolism. All these findings totally go beyond our expectation and open up a bran-new world for prokaryote lysine-acetyaltion modulation.
In order to check the physiology of the lysine-acetylation on fermentation or non-fermentation carbon sources, in the second part, we constructed the null strains of S. enterica protein acetyltransferase (Pat) and the deacetylase (CobB) by using PCR mediated Red recombination technology and then cultured them on the glucose or citrate minimal medium. We find out S. enterica and its derivates exhibit different phenotypes on different carbon source minimal media and confirm the closer relation between revisable acetylation modification and energy metabolism. Moreover, we propose that so far the Pat and CobB may be the only known enzymes responsible for the revisable acetylation modification of the key metabolism enzymes.
In the third part, we cloned and expressed the Pat, CobB and other proteins concerned with central energy metabolism, such as glyceraldehydes-3-phosphate dehydrogenase (GapA), isocitrate dehydrogenase kinase/phosphatase (AceK) and isocitrate lyase (AceA) in E. coli and S. enterica, then reconstructed the acetylation/deacetylation modification system in vitro by Pat or/and CobB to check whether these enzymes' activity regulated by lysine-acetylation. Furthermore, we constructed the GapA, AceK and AceA's site-directed mutant protein and null mutant strains and assayed their activities in vitro to study the specific modification sites. The results indicate that the GapA's dehydrogenation activity is directly proportioned with its acetylation level, and while the AceK's kinase activity and AceA's lyase activity are negative related with acetylation level. Moreover, the108,115,321 and 331 lysines of GapA, the 72,83 and 553 lysines of AceK, and the 13 and 308 lysines of AceA are closely correlated with acetylation modification.
In the fourth part, we used the quantity Real-time PCR, choosing the 16S rRNA as internal transcriptional controls, to check the transcription of Pat and CobB in different metabolism pathways. The results reveal that S. enterica in glucose medium has higher pat and cobB transcription levels than that in citrate medium under either mid log phase or stationary phas; Furthermore, for cells grew in either citrate or glucose, the transcription levels of pat and cobB in log phase were uniformly higher than that in stationary phase. Therefore, we put forward that the change of the ratio of pat mRNA/cobB mRNA, designed acetylation potential, between cells in the mid log phase versus in the stationary phase. Through qRT-PCR study, we validate the relation between acetylation modification are coordinated with the change of carbon sources.
In summary, the findings described in this thesis provide direct biochemical, physiological, and genetic data supporting the hypothesis that reversible lysine acetylation modification plays is a key and extensive role of global regulation of central metabolic circuits. Taking the advantage of a single pair of acetylase and deacetylase targeting metabolic enzymes in S. enterica, we demonstrate that the molecular mechanism achieving this regulation is through coupled transcription variation of de/acetylase (cobB/pat) genes and reversible lysine acetylation of metabolic enzymes in response to the change of carbon sources. Consistent with our collaborator's study in mammalian cells that showed a general role of acetylation in metabolism regulation, we propose that reversible lysine acetylation of metabolic enzymes represents an evolutionarily conserved universal mechanism in metabolic regulation in both eukaryote and prokaryotes.
All these results open up a new field of acetyaltion modification in prokaryote.
本论文利用赖氨酸乙酰化抗体的特异性,结合免疫沉淀和质谱技术的高效分离特性,首次对原核生物Salmonella enterica的乙酰化底物蛋白进行了蛋白组学水平的扫描,揭示乙酰化修饰与各种代谢关系密切；以可发酵碳源葡萄糖和不可发酵碳源柠檬酸为碳源,研究乙酰化修饰与不同代谢途径之间的关系,并且从表型、生化和遗传三个水平深入研究了乙酰化修饰对S. enterica中心代谢的调控机制,首次揭示赖氨酸可逆乙酰化修饰是中心代谢在整体水平上的一种调控方式；同时结合我们合作实验室关于真核生物乙酰化修饰的研究结果,提出赖氨酸可逆乙酰化修饰是一种广泛存在于真核和原核生物中的非常保守的中心代谢的调控机制。
整个研究分为以下四个部分展开。
第一部分我们利用免疫沉淀的高灵敏性富集赖氨酸乙酰化肽段,并利用质谱技术的高分辨率,首次对原核生物S. enterica的赖氨酸乙酰化修饰底物蛋白在蛋白组学水平上进行了扫描研究,得到一系列与能量代谢、转录调控、氨基酸和核酸合成等密切相关的乙酰化修饰底物蛋白。本试验结果发现有166个蛋白的190个肽段是乙酰化的,且其中的77个蛋白是与代谢相关的,这大大超出了我们对乙酰化修饰的预期,为原核生物的乙酰化研究开辟了一个新的天地。
第二部分我们采用Red重组技术成功获得了S. enterica的乙酰基转移酶(Pat)和/或去乙酰化酶(CobB)缺失的突变株,并对它们在葡萄糖和柠檬酸为唯一碳源的基本培养基上的生长表型进行了研究,结果发现S. enterica及其衍生菌株在不同碳源基本培养基中展示出截然不同的生长表型,确认了乙酰化修饰与S. enterica能量代谢之间的密切关系,并提出乙酰基转移酶(Pat)和去乙酰化酶(CobB)可能是目前唯一已知的能够对S. enterica中心代谢关键酶起可逆乙酰化修饰调控的乙酰化修饰酶。
第三部分我们克隆并表达了乙酰基转移酶(Pat)和去乙酰化酶(CobB)以及中心代谢关键酶,如3-磷酸甘油醛脱氢酶(GapA)、异柠檬酸脱氢酶激酶/磷酸化酶(AceK)和异柠檬酸裂解酶(AceA),并在体外重构Pat/CobB介导的乙酰化/去乙酰化修饰体系,研究乙酰化修饰对这些酶活性的调控方式；同时构建GapA、AceK和AceA乙酰化修饰位点的点突变蛋白和敲除突变株,体外测定酶活力变化,研究这三个酶的具体乙酰化修饰位点,并进行表型互补试验。结果发现GapA的脱氢酶活力与乙酰化修饰正相关,而AceK的激酶活力和AceA裂解酶活力与乙酰化修饰负相关,且GapA的第108、115、321和331位赖氨酸,AceK的第72、83和553位赖氨酸,AceA的第13和308位赖氨酸与乙酰化修饰密切相关。
第四部分我们以核糖体RNA 16S rRNA为内参基因,利用定量荧光实时PCR研究乙酰基转移酶(Pat)和去乙酰化酶(CobB)的转录与不同代谢途径乙酰化修饰之间的关系,结果显示：在葡萄糖为碳源的情况下,pat和cobB的转录水平要高于柠檬酸为碳源；不管是葡萄糖还是以柠檬酸为碳源,对数期pat和cobB的转录水平均要高于它们在稳定期和迟滞期的转录水平；提出存在一个乙酰化潜能(pat mRNA/cobB mRNA)的概念,即pat和cobB的转录水平决定了不同时期的乙酰化修饰水平。通过qRT-PCR试验,在转录水平验证了乙酰化修饰与不同碳源代谢之间的相互关系。
综上所述,本论文综合乙酰化修饰在生理、生化和遗传三个方面的证据,验证了乙酰化修饰是一种广泛存在于原核生物S. enterica中的调控方式；提出S.enterica不同代谢通路转换的分子机制是通过乙酰基转移酶(Pat)和去乙酰化酶(CobB)的共同作用,对中心代谢关键酶类如GapA, AceA和AceK等进行可逆的乙酰化修饰,从整体水平上调控中心代谢；结合我们合作伙伴在真核生物中的研究结果,我们认为代谢关键酶类赖氨酸残基的可逆乙酰化修饰不管是在原核生物还是在真核生物中,在进化上都是一种非常保守的调控机制。
以上结果为原核生物的乙酰化修饰研究开辟了一个新的领域。
Protein post-translation modification is an important content of epigenetics. The pivotal importance of lysine-acetylation and its regulatory enzymes to the several fundamental cellular processes in mammalian cells, including histone modification, calorie restriction, cell apoptosis, life span extension, transcription silencing and so on, continues to be revealed at a remarkable pace. Recently, the study of lysine-acetylation in eukaryote changes with each passing day, and while the extent and function of this modification in prokaryotic remain largely unexplored because of the absence of research means and weak basis, thereby presenting a hurdle to further functional study of this modification in prokaryotic systems.
Here we reported the first global scanning of lysine-acetylation in the prokaryote S. enterica by efficient affinity enrichment of lysine acetylated peptide with homemade lysine-acetylation antibody, combining with the high resolving power of immunoprecipitation and mass spectrum, and subsequently do the further study of these acetylation substrate enzymes of S. enterica central metabolism and energy metabolism from the physiological, biochemical, and genetic levels. Integrating with our collaborator's eukaryote results, we propose that reversible lysine acetylation of metabolic enzymes is the mechanism of global regulation of the central metabolism circuits and represents an evolutionarily conserved universal mechanism in metabolic regulation in both eukaryote and prokaryotes.
Our study includes four parts.
In the first part, we firstly applied the high sensitivity of immunoprecipitation to enrich the lysine acetylated peptides and did the proteomics screening of lysine-acetylation substrate proteins in S. enterica, whereafter used the high resolution of HPLC/mass spectrometer to identify acetylated peptides. The screening identified a series of acetylated substrate proteins correlated with energy metabolism, transcription modulation, amino acid and nucleic acid biosynthesis and so on. We discover that 190 modification sites in 166 proteins from S. enterica are acetylated, of which 77 proteins are correlated with metabolism. All these findings totally go beyond our expectation and open up a bran-new world for prokaryote lysine-acetyaltion modulation.
In order to check the physiology of the lysine-acetylation on fermentation or non-fermentation carbon sources, in the second part, we constructed the null strains of S. enterica protein acetyltransferase (Pat) and the deacetylase (CobB) by using PCR mediated Red recombination technology and then cultured them on the glucose or citrate minimal medium. We find out S. enterica and its derivates exhibit different phenotypes on different carbon source minimal media and confirm the closer relation between revisable acetylation modification and energy metabolism. Moreover, we propose that so far the Pat and CobB may be the only known enzymes responsible for the revisable acetylation modification of the key metabolism enzymes.
In the third part, we cloned and expressed the Pat, CobB and other proteins concerned with central energy metabolism, such as glyceraldehydes-3-phosphate dehydrogenase (GapA), isocitrate dehydrogenase kinase/phosphatase (AceK) and isocitrate lyase (AceA) in E. coli and S. enterica, then reconstructed the acetylation/deacetylation modification system in vitro by Pat or/and CobB to check whether these enzymes' activity regulated by lysine-acetylation. Furthermore, we constructed the GapA, AceK and AceA's site-directed mutant protein and null mutant strains and assayed their activities in vitro to study the specific modification sites. The results indicate that the GapA's dehydrogenation activity is directly proportioned with its acetylation level, and while the AceK's kinase activity and AceA's lyase activity are negative related with acetylation level. Moreover, the108,115,321 and 331 lysines of GapA, the 72,83 and 553 lysines of AceK, and the 13 and 308 lysines of AceA are closely correlated with acetylation modification.
In the fourth part, we used the quantity Real-time PCR, choosing the 16S rRNA as internal transcriptional controls, to check the transcription of Pat and CobB in different metabolism pathways. The results reveal that S. enterica in glucose medium has higher pat and cobB transcription levels than that in citrate medium under either mid log phase or stationary phas; Furthermore, for cells grew in either citrate or glucose, the transcription levels of pat and cobB in log phase were uniformly higher than that in stationary phase. Therefore, we put forward that the change of the ratio of pat mRNA/cobB mRNA, designed acetylation potential, between cells in the mid log phase versus in the stationary phase. Through qRT-PCR study, we validate the relation between acetylation modification are coordinated with the change of carbon sources.
In summary, the findings described in this thesis provide direct biochemical, physiological, and genetic data supporting the hypothesis that reversible lysine acetylation modification plays is a key and extensive role of global regulation of central metabolic circuits. Taking the advantage of a single pair of acetylase and deacetylase targeting metabolic enzymes in S. enterica, we demonstrate that the molecular mechanism achieving this regulation is through coupled transcription variation of de/acetylase (cobB/pat) genes and reversible lysine acetylation of metabolic enzymes in response to the change of carbon sources. Consistent with our collaborator's study in mammalian cells that showed a general role of acetylation in metabolism regulation, we propose that reversible lysine acetylation of metabolic enzymes represents an evolutionarily conserved universal mechanism in metabolic regulation in both eukaryote and prokaryotes.
All these results open up a new field of acetyaltion modification in prokaryote.
引文
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