德氏乳杆菌保加利亚亚种CAUH1酸耐受机制的蛋白组学研究及抗酸胁迫基因Ldb0677和pyk的功能分析
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摘要
酸奶对人体具有重要益生保健功能,但是后酸化问题一直以来制约着酸奶行业发展。研究表明控制发酵后期德氏乳杆菌保加利亚亚种(Lactobacillus delbrueckii subsp. bulgaricus)的生长代谢是解决后酸化的关键。本研究采用蛋白组学技术和转录水平分析相结合的研究手段,对L.bulgaricus CAUH1酸胁迫反应中的关键基因进行分离和功能鉴定,研究结果为全面揭示L.bulgaricus酸耐受机制奠定基础,为解决酸奶后酸化问题提供理论依据。研究内容及结果如下
(1) L. bulgaricus CAUH1酸胁迫条件下差异蛋白的分离鉴定及转录水平分析。应用2-DE方法和MALDI-TOF/TOF-MS/MS质谱成功鉴定了26个差异蛋白。利用反转录-实时定量PCR方法分析CAUH1抗酸胁迫的差异蛋白在转录水平上变化,结果表明差异基因在蛋白水平上的变化同其在转录水平上的变化趋势一致。这说明L. bulgaricus CAUH1在应对酸胁迫时,一系列关键基因的表达主要是在转录水平上进行调控的。
(2)生物信息学分析L. bulgaricus酸耐受反应机制。利用生物信息学分析差异基因的功能及参与的代谢途径,结果表明：在应对酸胁迫过程中,L. bulgaricus CAUH1提高了糖酵解途径相关酶的表达量,以加强碳水化合物分解代谢和能量供应；调整了丙酮酸代谢产物去向,使之进入脂肪酸合成途径,以提高细胞膜中饱和脂肪酸比例,增强膜的硬度和不透性；改变了延伸因子EF-Tu、EF-G和核糖体蛋白RpsA的表达量,来降低胞内蛋白的合成速率,提高蛋白合成时翻译的精确性。
(3)抗酸胁迫差异基因的异源超量表达及功能验证。利用乳酸乳球菌NICE表达系统对6个抗酸胁迫差异基因进行超量表达,结果表明pyk的超量表达能够提高宿主菌在酸致死条件下的存活率45倍,Ldb0677的超量表达能够提高宿主菌的存活率200倍。通过SDS-PAGE检测到Pyk和Ldb0677蛋白的成功表达,进一步证实这两个蛋白在菌体酸耐受过程中的作用。另外,Ldb0677的超量表达还能够提高宿主菌对于胆盐的抗性,而Pyk的超量表达不仅提高了宿主菌对于胆盐胁迫的抗性,还提高了菌体对冷胁迫的抗性。
(4)抗酸胁迫反应中新转录因子Ldb0677的功能研究。利用细菌单杂交系统确定了假定蛋白Ldb0677的DNA结合位点的保守基序SSTAGACR,通过DNA结合位点的序列特征预测出22个由Ldb0677调控的靶基因。采用乳酸乳球菌NICE系统表达带有组氨酸标签的Ldb0677蛋白,并通过镍柱亲和层析得到纯化的Ldb0677。利用EMSA实验体外验证了Ldb0677蛋白同靶基因LBU_1764和Ldb0486的特异性结合。结果表明,Ldb0677作为一个新的转录因子参与L. bulgaricus的酸耐受反应。
(5)调控抗酸胁迫基因pyk表达的转录因子的分离鉴定。从L. bulgaricus CAUH1中克隆了65个转录因子,基于pB1H2w2-Prd载体构建了转录因子文库并通过Western blot确定了文库中转录因子同Omega亚基的融合表达。采用缺失序列法构建了无自激活现象的“诱饵”载体,并利用“诱饵”载体通过细菌单杂交实验从转录因子文库中筛选出调控pyk基因的转录因子——分解代谢物控制蛋白CcpA。生物信息学分析表明CcpA的结合位点位于pfk-pyk操纵子的启动子-35区上游,其序列为TGTAAGCCCTAACA。
Yoghurt has been considered beneficial to the human health, but post-acidification has been a serious problem which restricts the development of yogurt industry. Previous studies indicate that controlling the growth of Lactobacilus delbrueckii subsp. bulgaricus is the key to solve the post-acidification. In this study, proteomics approach complemented by transcriptional analysis was employed to separate and identify the proteins which were differentially expressed in response to acid stress, and further characterize their function during acid adaptation. This study will get more useful information for comprehensively understanding the mechanism of acid tolerance response in L. bulgaricus, meanwhile the results will also provide new insights and ideas for resolving the post-acidification problem in the yoghurt production and storage. The research contents and results in this dissertation were as followed.
(1) Identification and transcriptional analysis of the proteins which were differentially expressed in L. bulgaricus CAUH1under acid stress. Twenty seven proteins were separated by2-DE approach and identified by MALDI-TOF/TOF-MS/MS. The changes of these proteins in L. bulgaricus CAUH1at transcription level were detected using real-time reverse transcription PCR. These results also demonstrated that all the changes in protein levels were accompanied by concordant changes in the expression of corresponding mRNAs, which further revealed that the expression of some key genes were regulated mainly at transcriptional level in L. bulgaricus under acid stress condition.
(2) Bioinformatics analysis of the mechanism of acid tolerance response in L. bulgaricus. The metabolic pathways participated by the differently expressing genes and their functions were studied using bioinformatics analysis, revealing that when grown under acid stress condition, L. bulgaricus CAUH1enhanced the expression of glycolysis-associated enzymes to improve the carbohydrate catabolism and energy supply; rerouted the pyruvate metabolism to fatty acid biosynthesis to increase the ratio of saturated fatty acids in the cell membrane and enhance the rigidity and impermeability of the membrane; modulated the abundance of elongation factors (EF-Tu, EF-G) and ribosomal protein S1(RpsA) to reduce the rate of protein synthesis and enhance the translational accuracy.
(3) Functional identification of acid stress-related genes by heterologous over-expression. Heterologous over-expression of six acid stress-related genes were carried out using the L. lactis NICE system. The results indicated that Pyk-overproducing strain showed45-fold increase in survival under acid stress condition and Ldb0677-overproducing strain showed200-fold increase in survival. SDS-PAGE indicated that Pyk and Ldb0677were successfully expressed, thus these two protein were considered to play important roles in acid tolerance response. In addtion, over-expression of Ldb0677also enhanced the bile resistance of the host strain. Over-expression of Pyk enhanced the bile and cold resistance of the host strain.
(4) Characterization of a novel acid stress-related transcription factor Ldb0677. The DNA-binding motif (SSTAGACR) of Ldb0677was determined using bacterial one-hybrid. Twenty two target genes were predicted according to the DNA-binding sequence feature. The Ldb0677with a His-tag was expressed using L. lactis NICE system, and purified through Nickel-affinity chromatography column. And the DNA-binding specificity of Ldb0677to target genes LBU_1764and Ldb0486were further assessed by electrophoretic mobility shift assay (EMSA), respectively. These results indicated that Ldb0677was a novel transcription factor and might function as a major regulator in acid stress response in L. bulgaricus.
(5) Identification of the transcription factor which regulates the acid stress-related gene pyk. Sixty five transcription factor genes were amplified by PCR from the genomic DNA of L. bulgaricus CAUH1and inserted into pB1H2w2to generate the L. bulgaricus transcription factor library. Western blot results confirmed that each TF had expressed as a carboxy-terminal fusion to the omega-subunit. The "Bait" vectors with no self-activation were constructed by deletion analysis method. The transcription factor which regulated the expression of pyk gene was identified to be the catabolite control protein A (CcpA) using the transcription factor library complemented by bacterial one-hybrid assay. Moreover, the binding site of CcpA was predicted to be upstream the-35region, and the sequence was TGTAAGCCCTAACA.
(1) L. bulgaricus CAUH1酸胁迫条件下差异蛋白的分离鉴定及转录水平分析。应用2-DE方法和MALDI-TOF/TOF-MS/MS质谱成功鉴定了26个差异蛋白。利用反转录-实时定量PCR方法分析CAUH1抗酸胁迫的差异蛋白在转录水平上变化,结果表明差异基因在蛋白水平上的变化同其在转录水平上的变化趋势一致。这说明L. bulgaricus CAUH1在应对酸胁迫时,一系列关键基因的表达主要是在转录水平上进行调控的。
(2)生物信息学分析L. bulgaricus酸耐受反应机制。利用生物信息学分析差异基因的功能及参与的代谢途径,结果表明：在应对酸胁迫过程中,L. bulgaricus CAUH1提高了糖酵解途径相关酶的表达量,以加强碳水化合物分解代谢和能量供应；调整了丙酮酸代谢产物去向,使之进入脂肪酸合成途径,以提高细胞膜中饱和脂肪酸比例,增强膜的硬度和不透性；改变了延伸因子EF-Tu、EF-G和核糖体蛋白RpsA的表达量,来降低胞内蛋白的合成速率,提高蛋白合成时翻译的精确性。
(3)抗酸胁迫差异基因的异源超量表达及功能验证。利用乳酸乳球菌NICE表达系统对6个抗酸胁迫差异基因进行超量表达,结果表明pyk的超量表达能够提高宿主菌在酸致死条件下的存活率45倍,Ldb0677的超量表达能够提高宿主菌的存活率200倍。通过SDS-PAGE检测到Pyk和Ldb0677蛋白的成功表达,进一步证实这两个蛋白在菌体酸耐受过程中的作用。另外,Ldb0677的超量表达还能够提高宿主菌对于胆盐的抗性,而Pyk的超量表达不仅提高了宿主菌对于胆盐胁迫的抗性,还提高了菌体对冷胁迫的抗性。
(4)抗酸胁迫反应中新转录因子Ldb0677的功能研究。利用细菌单杂交系统确定了假定蛋白Ldb0677的DNA结合位点的保守基序SSTAGACR,通过DNA结合位点的序列特征预测出22个由Ldb0677调控的靶基因。采用乳酸乳球菌NICE系统表达带有组氨酸标签的Ldb0677蛋白,并通过镍柱亲和层析得到纯化的Ldb0677。利用EMSA实验体外验证了Ldb0677蛋白同靶基因LBU_1764和Ldb0486的特异性结合。结果表明,Ldb0677作为一个新的转录因子参与L. bulgaricus的酸耐受反应。
(5)调控抗酸胁迫基因pyk表达的转录因子的分离鉴定。从L. bulgaricus CAUH1中克隆了65个转录因子,基于pB1H2w2-Prd载体构建了转录因子文库并通过Western blot确定了文库中转录因子同Omega亚基的融合表达。采用缺失序列法构建了无自激活现象的“诱饵”载体,并利用“诱饵”载体通过细菌单杂交实验从转录因子文库中筛选出调控pyk基因的转录因子——分解代谢物控制蛋白CcpA。生物信息学分析表明CcpA的结合位点位于pfk-pyk操纵子的启动子-35区上游,其序列为TGTAAGCCCTAACA。
Yoghurt has been considered beneficial to the human health, but post-acidification has been a serious problem which restricts the development of yogurt industry. Previous studies indicate that controlling the growth of Lactobacilus delbrueckii subsp. bulgaricus is the key to solve the post-acidification. In this study, proteomics approach complemented by transcriptional analysis was employed to separate and identify the proteins which were differentially expressed in response to acid stress, and further characterize their function during acid adaptation. This study will get more useful information for comprehensively understanding the mechanism of acid tolerance response in L. bulgaricus, meanwhile the results will also provide new insights and ideas for resolving the post-acidification problem in the yoghurt production and storage. The research contents and results in this dissertation were as followed.
(1) Identification and transcriptional analysis of the proteins which were differentially expressed in L. bulgaricus CAUH1under acid stress. Twenty seven proteins were separated by2-DE approach and identified by MALDI-TOF/TOF-MS/MS. The changes of these proteins in L. bulgaricus CAUH1at transcription level were detected using real-time reverse transcription PCR. These results also demonstrated that all the changes in protein levels were accompanied by concordant changes in the expression of corresponding mRNAs, which further revealed that the expression of some key genes were regulated mainly at transcriptional level in L. bulgaricus under acid stress condition.
(2) Bioinformatics analysis of the mechanism of acid tolerance response in L. bulgaricus. The metabolic pathways participated by the differently expressing genes and their functions were studied using bioinformatics analysis, revealing that when grown under acid stress condition, L. bulgaricus CAUH1enhanced the expression of glycolysis-associated enzymes to improve the carbohydrate catabolism and energy supply; rerouted the pyruvate metabolism to fatty acid biosynthesis to increase the ratio of saturated fatty acids in the cell membrane and enhance the rigidity and impermeability of the membrane; modulated the abundance of elongation factors (EF-Tu, EF-G) and ribosomal protein S1(RpsA) to reduce the rate of protein synthesis and enhance the translational accuracy.
(3) Functional identification of acid stress-related genes by heterologous over-expression. Heterologous over-expression of six acid stress-related genes were carried out using the L. lactis NICE system. The results indicated that Pyk-overproducing strain showed45-fold increase in survival under acid stress condition and Ldb0677-overproducing strain showed200-fold increase in survival. SDS-PAGE indicated that Pyk and Ldb0677were successfully expressed, thus these two protein were considered to play important roles in acid tolerance response. In addtion, over-expression of Ldb0677also enhanced the bile resistance of the host strain. Over-expression of Pyk enhanced the bile and cold resistance of the host strain.
(4) Characterization of a novel acid stress-related transcription factor Ldb0677. The DNA-binding motif (SSTAGACR) of Ldb0677was determined using bacterial one-hybrid. Twenty two target genes were predicted according to the DNA-binding sequence feature. The Ldb0677with a His-tag was expressed using L. lactis NICE system, and purified through Nickel-affinity chromatography column. And the DNA-binding specificity of Ldb0677to target genes LBU_1764and Ldb0486were further assessed by electrophoretic mobility shift assay (EMSA), respectively. These results indicated that Ldb0677was a novel transcription factor and might function as a major regulator in acid stress response in L. bulgaricus.
(5) Identification of the transcription factor which regulates the acid stress-related gene pyk. Sixty five transcription factor genes were amplified by PCR from the genomic DNA of L. bulgaricus CAUH1and inserted into pB1H2w2to generate the L. bulgaricus transcription factor library. Western blot results confirmed that each TF had expressed as a carboxy-terminal fusion to the omega-subunit. The "Bait" vectors with no self-activation were constructed by deletion analysis method. The transcription factor which regulated the expression of pyk gene was identified to be the catabolite control protein A (CcpA) using the transcription factor library complemented by bacterial one-hybrid assay. Moreover, the binding site of CcpA was predicted to be upstream the-35region, and the sequence was TGTAAGCCCTAACA.
引文
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