半滑舌鳎（Cynoglossus semilaevis）TLR9及其信号传导相关基因的克隆与表达
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摘要
半滑舌鳎(Cynoglossus semilaevis),为温水性近海底层鱼类,在我国沿海均有分布,尤以渤海、黄海为多。随着消费需求的增加,其养殖业迅速发展,已成为北方海水养殖业的重要组成部分。由于工厂化养殖规模的扩大,养殖环境不断恶化、半滑舌鳎抗病力下降,病害时有发生,造成巨大的经济损失。因此,深入研究半滑舌鳎免疫防御机制,探讨提高机体抗病力的有效途径和方法,改良种质和培育抗病品系,无疑是解决目前困扰半滑舌鳎工厂化养殖的有效途径。
Toll样受体(TLRs)家族的研究源于果蝇Toll受体的发现,果蝇的Toll受体一方面参与发育时期体轴的形成,一方面参与抵御病毒、细菌和真菌感染,介导先天性免疫反应。TLRs是重要的模式识别受体(PRRs),参与识别病原体相关的分子模式(PAMPs),在天然免疫系统中起着非常重要的作用。哺乳动物中TLR信号通路还参与诱导树突状细胞成熟、参与免疫耐受、参与凋亡发生发展、介导非感染性因素的识别等,被视为联系先天性免疫和获得性免疫的桥梁。TLR9作为TLRs家族中的成员,主要针对性识别细菌或病毒基因组内非甲基化DNA(CpG DNA)序列,启动信号通路。本研究以同源克隆的方法获得了半滑舌鳎TLR9及其信号通路相关基因的全长cDNA,并通过研究TLR9及其信号通路相关基因在不同组织和发育时期以及灭活鳗弧菌刺激后的表达情况,初步了解TLR9及其信号通路相关基因在半滑舌鳎免疫识别中的作用。
1半滑舌鳎TLR9基因的克隆及表达分析
根据genebank中已提交的鱼类及哺乳类TLR9序列保守区域设计简并引物得到核心片段,通过RACE技术获得3’及5’末端,经拼接后得到半滑舌鳎TLR9 cDNA全序列。根据已得到的cDNA序列,设计跨ORF引物,以DNA为模板,获得半滑舌鳎TLR9基因全长。csTLR9基因序列包括3个外显子,2个内含子;其cDNA序列由23 bp 5’UTR,342 bp 3’UTR以及3186 bp ORF组成,其ORF编码1062个aa,包含胞外区14个富含亮氨酸的基序(LRR motif),跨膜区(TM)和胞内TIR结构域(TIR domain)。csTLR9与金头鲷和牙鲆TLR9同源性高于60%。Real time PCR结果显示csTLR9广泛表达于各个组织中,尤其是脾脏和性腺中表达量很高。免疫刺激试验表明,注射灭活鳗弧菌后,半滑舌鳎脾脏和头肾中TLR9的表达量没有显著变化。发育阶段TLR9表达分析发现母源性TLR9 mRNA的存在,且在变态时期TLR9表达量显著降低,暗示TLR9可能参与半滑舌鳎个体发育,在其发育过程中发挥了重要的作用。虽然存在物种间差异,但csTLR9无论是在序列上,还是在表达方面都表现出与其他鱼类及哺乳动物的相似性。
2半滑舌鳎MyD88基因的克隆及表达分析
MyD88是IL-1R/TLR超家族胞内信号传导中重要的接头蛋白。半滑舌鳎MyD88基因全长2855 bp,包含5个外显子,4个内含子;其cDNA包含110 bp 5’UTR,576 bp 3’UTR和编码285 aa的编码区。csMyD88与其他鱼类及哺乳类MyD88序列相似性很高,与牙鲆MyD88相似性高于70%。csMyD88包含一个TIR结构域,一个致死域(DD)及连接二者的中间区域(ID)。RT-PCR结果表明csMyD88在不同组织中的表达情况与TLR9类似,在所检测的12种组织中csMyD88都有表达,尤其在脾脏和性腺中表达水平很高。腹腔注射灭活鳗弧菌后,半滑舌鳎脾脏和头肾中MyD88的表达水平显著升高。在半滑舌鳎的发育过程中,csMyD88的表达量表现出随发育时期而变化的特征。csMyD88与其他脊椎动物在序列上及表达特征上的相似性,暗示脊椎动物MyD88在功能及作用机制上的保守性。
3半滑舌鳎IRAK4基因的克隆及表达分析
IRAK4在TLR/IL-1R超家族信号转导中具有重要的地位。IRAK4通过磷酸化IRAK1的KD区,激活IRAK1,将信号向下传导。通过拼接核心片段、3’及5’末端得到csIRAK4 cDNA全序列,包括5’UTR 168 bp,3’UTR 580 bp以及ORF 1401 bp。SMART分析表明csIRAK4包含一个典型S_TKc结构域(serine/threonine kinases catalytic domain)和一个致死域。csIRAK4与其他鱼类IRAK4同源性不高,低于50%。在所检测的12种组织中,半滑舌鳎IRAK4都存在表达,尤其是在脾脏、鳍、头肾以及性腺中表达水平很高。Real time PCR结果显示csIRAK4的表达水平在不同发育时期有显著性差异,这与发育时期TLR9及MyD88的表达趋势类似,暗示包含TLR9、MyD88和IRAK4在内的TLR9信号通路可能参与了半滑舌鳎的发育过程。
4半滑舌鳎IL-1β基因的克隆及表达分析
炎症反应是抵抗病原体入侵的第一道防线,IL-1β所属白介素-1家族是一簇炎前细胞因子,一旦免疫刺激发生,作为炎症反应中的重要部分,IL-1家族成员的表达量会显著增加,对抗微生物的入侵。例如,当TLR受体识别外来病原后,通过特定的信号通路最终将激活IL-1家族成员的大量表达。csIL-1βcDNA全长,包括5’UTR 130 bp,3’UTR 417 bp以及编码区741 bp,其中3’UTR中包含5个不稳定基序(ATTTA)以及1个加尾信号(AATAAA)。完整的ORF编码246 aa,含有一个典型的IL-1家族特征序列,但未发现interleukin-1- converting enzyme(ICE)识别位点。同源性比较结果显示csIL-1β与大菱鲆IL-1β有64%的同源性。组织表达分析表明csIL-1β与TLR9、MyD88、IRAK4类似,也具有广泛的表达谱,在12中检测组织中都有表达,尤其是免疫相关组织表达量高;不同的是csIL-1β在性腺中表达水平较低。腹腔注射后半滑舌鳎脾脏和头肾中IL-1β的表达量开始增加,并于注射后8 h达到最高点,随后逐渐降低,于注射后48 h恢复至注射前表达水平。
Half-smooth tongue sole (Cynoglossus semilaevis) is a large flatfish species widely distributed alone the coast of China. Because of its good taste and nutrition, C. semilaevis is considered as a commercially important marine fishery resource which is being widely cultured in china. Vibrio anguillarum, a kind of Gram-negative bacterium that causes hemorrhagic septicemia in fishis, is a significant threat to commercial production in marine aquaculture. The cloning of the immune related genes and the research of immune mechanism is helpful to select strains of fish with enhanced resistance to some major diseases.
Toll-like receptors (TLRs) are considered as key sensors to trigger the host’s innate immune system and adaptive immune responses by recognizing various PAMPs and initiating signal transduction. TLR9, as a member of TLR family, mediates the recognition of unmethylated CpG dinucleotide motifs commonly found in both bacterial and viral genomes. In the current study, the TLR9 gene was isolated from one of flatfish species, C. semilaevis. In the 4588 bp genomic sequence, three exons, two introns, and 5’UTR of 23 bp and 3’UTR of 342 bp were identified. Putative amino acid sequence was 1062 residues long, including a typical conserved cytosolic Toll/interleukin-1 receptor (TIR) domain, 14 leucine-rich repeat (LRR) motifs, with greater than 60% identity to gilthead sea bream Sparus aurata and Japanese flounder Paralichthys olivaceus orthologs. Quantitative RT-PCR analysis indicated a broad expression of csTLR9, especially in spleen and gonads. No statistically significant changes were observed for csTLR9 mRNA levels in spleen and head kidney after inactive V. anguillarum immunisation. In C. semilaevis ontogeny, the expression of csTLR9 appeared to be developmentally regulated. The presence of maternal TLR9 mRNA and the dramatic decrease of TLR9 expression at metamorphic stage indicated TLR9 might be involved in C. semilaevis development. Comparing sequence and expression profile of csTLR9 with mammalian and other piscine TLR9s suggested that the main function of TLR9 might be conserved across vertebrates, although species-specific features were present.
Myeloid differentiation factor 88 (MyD88) is a universal and crucial adaptor protein, which plays an essential role in the intracellular signaling elicited by IL-1R/TLR superfamily. In the present study, we report the full-length sequence of MyD88 gene in C. semilaevis. In the 2855 bp genomic sequence, five exons and four introns were identified. The cloned cDNA exhibited 110 bp of 5’UTR, 576 bp of 3’UTR and 858 bp of the entire open reading frame encoding a polypeptide of 285 amino acids. The protein sequence included a typical conserved cytosolic Toll/interleukin-1 receptor (TIR) domain, an intermediate domain (ID) and a death domain (DD), and shared greater than 70% identity with Japanese flounder P. olivaceu ortholog. RT-PCR analysis indicated a broad expression of csMyD88, especially in ovary and spleen. Quantitative RT-PCR analysis indicated that the csMyD88 mRNA levels were significantly increased in the spleen and head kidney after inactive V. anguillarum challenge and the expression of csMyD88 appeared to be developmentally regulated during C. semilaevis ontogeny. Although, species-specific differences were present, the similarity between mammalian and piscine MyD88s suggested that the main function of MyD88 might be conserved across vertebrates.
IL-1 receptor-associated kinases (IRAKs) are important mediators in the signal transduction of IL-1R/TLR superfamily members. IRAK4 is able to phosphorylate IRAK1, and overexpression of dominant-negative IRAK4 is blocking the IL-1-induced activation and modification of IRAK1, suggesting a role of IRAK4 as a central element in the early signal transduction of IL-1R/TLR receptors, upstream of IRAK1. The IRAK4 cDNA encodes a protein with 466 amino acids and a calculated molecular mass of 52 kDa. Analysis of the deduced protein sequence revealed an N-terminal death domain and a central kinase domain (S_TKc domain). The overall sequence identity shared between csIRAK4 and other fish orthologs is low, between 40-50%. A broader analysis of a tissue cDNA panel by RT-PCR revealed different level of expressions in a wide variety of tissues. The strongest expression level was observed in spleen、fin、head kidney and gonads samples. The maternal mRNA of IRAK4 in unfertilised eggs and the dramatic decrease of IRAK4 expression level during metamorphosis suggested the important role of IRAK4 in C. semilaevis development.
Interleukin-1 (IL-1) is a pleiotropic paracrine and endocrine signaling molecule and is produced by a variety of cell types. The major functions of IL-1βare activation of the proliferation of such lymphocytes as T cells and B cells, activation of cytotoxic activity in macrophage and natural killer (NK) cells, and induction of immunoglobulin (Ig) secretion. The full-length cDNA sequence of IL-1βfrom the C. semilaevis was determined by using PCR with primers designed from known fish IL-1βsequences followed by elongation of the 5’and 3’ends using RACE. The cDNA contains 130 bp 5’UTR, a single ORF of 741 bp that translates into a 247 aa molecule, 417 bp 3’UTR with five cytokine RNA instability motifs (ATTTA), and a polyadenylation signal (AATAAA) at 15 nucleotides upstream of the poly(A) tail. The deduced aa of csIL-1βshowed the highest identity (64%) with Scophthalmus maximus IL-1β. csIL-1βgene was strongly expressed in spleen, fin and head kidney and weakly expressed in muscle. After stimulation with V. anguillarum, we found a significantly increased level of IL-1βexpression in head kidney and spleen compared to that of blank control. In the head kidney and spleen of C. semilaevis stimulated by inactive V. anguillarum showed a peak level of IL-1βexpression at 8 h after intraperitoneal injection, and recovered at 48 h.
Toll样受体(TLRs)家族的研究源于果蝇Toll受体的发现,果蝇的Toll受体一方面参与发育时期体轴的形成,一方面参与抵御病毒、细菌和真菌感染,介导先天性免疫反应。TLRs是重要的模式识别受体(PRRs),参与识别病原体相关的分子模式(PAMPs),在天然免疫系统中起着非常重要的作用。哺乳动物中TLR信号通路还参与诱导树突状细胞成熟、参与免疫耐受、参与凋亡发生发展、介导非感染性因素的识别等,被视为联系先天性免疫和获得性免疫的桥梁。TLR9作为TLRs家族中的成员,主要针对性识别细菌或病毒基因组内非甲基化DNA(CpG DNA)序列,启动信号通路。本研究以同源克隆的方法获得了半滑舌鳎TLR9及其信号通路相关基因的全长cDNA,并通过研究TLR9及其信号通路相关基因在不同组织和发育时期以及灭活鳗弧菌刺激后的表达情况,初步了解TLR9及其信号通路相关基因在半滑舌鳎免疫识别中的作用。
1半滑舌鳎TLR9基因的克隆及表达分析
根据genebank中已提交的鱼类及哺乳类TLR9序列保守区域设计简并引物得到核心片段,通过RACE技术获得3’及5’末端,经拼接后得到半滑舌鳎TLR9 cDNA全序列。根据已得到的cDNA序列,设计跨ORF引物,以DNA为模板,获得半滑舌鳎TLR9基因全长。csTLR9基因序列包括3个外显子,2个内含子;其cDNA序列由23 bp 5’UTR,342 bp 3’UTR以及3186 bp ORF组成,其ORF编码1062个aa,包含胞外区14个富含亮氨酸的基序(LRR motif),跨膜区(TM)和胞内TIR结构域(TIR domain)。csTLR9与金头鲷和牙鲆TLR9同源性高于60%。Real time PCR结果显示csTLR9广泛表达于各个组织中,尤其是脾脏和性腺中表达量很高。免疫刺激试验表明,注射灭活鳗弧菌后,半滑舌鳎脾脏和头肾中TLR9的表达量没有显著变化。发育阶段TLR9表达分析发现母源性TLR9 mRNA的存在,且在变态时期TLR9表达量显著降低,暗示TLR9可能参与半滑舌鳎个体发育,在其发育过程中发挥了重要的作用。虽然存在物种间差异,但csTLR9无论是在序列上,还是在表达方面都表现出与其他鱼类及哺乳动物的相似性。
2半滑舌鳎MyD88基因的克隆及表达分析
MyD88是IL-1R/TLR超家族胞内信号传导中重要的接头蛋白。半滑舌鳎MyD88基因全长2855 bp,包含5个外显子,4个内含子;其cDNA包含110 bp 5’UTR,576 bp 3’UTR和编码285 aa的编码区。csMyD88与其他鱼类及哺乳类MyD88序列相似性很高,与牙鲆MyD88相似性高于70%。csMyD88包含一个TIR结构域,一个致死域(DD)及连接二者的中间区域(ID)。RT-PCR结果表明csMyD88在不同组织中的表达情况与TLR9类似,在所检测的12种组织中csMyD88都有表达,尤其在脾脏和性腺中表达水平很高。腹腔注射灭活鳗弧菌后,半滑舌鳎脾脏和头肾中MyD88的表达水平显著升高。在半滑舌鳎的发育过程中,csMyD88的表达量表现出随发育时期而变化的特征。csMyD88与其他脊椎动物在序列上及表达特征上的相似性,暗示脊椎动物MyD88在功能及作用机制上的保守性。
3半滑舌鳎IRAK4基因的克隆及表达分析
IRAK4在TLR/IL-1R超家族信号转导中具有重要的地位。IRAK4通过磷酸化IRAK1的KD区,激活IRAK1,将信号向下传导。通过拼接核心片段、3’及5’末端得到csIRAK4 cDNA全序列,包括5’UTR 168 bp,3’UTR 580 bp以及ORF 1401 bp。SMART分析表明csIRAK4包含一个典型S_TKc结构域(serine/threonine kinases catalytic domain)和一个致死域。csIRAK4与其他鱼类IRAK4同源性不高,低于50%。在所检测的12种组织中,半滑舌鳎IRAK4都存在表达,尤其是在脾脏、鳍、头肾以及性腺中表达水平很高。Real time PCR结果显示csIRAK4的表达水平在不同发育时期有显著性差异,这与发育时期TLR9及MyD88的表达趋势类似,暗示包含TLR9、MyD88和IRAK4在内的TLR9信号通路可能参与了半滑舌鳎的发育过程。
4半滑舌鳎IL-1β基因的克隆及表达分析
炎症反应是抵抗病原体入侵的第一道防线,IL-1β所属白介素-1家族是一簇炎前细胞因子,一旦免疫刺激发生,作为炎症反应中的重要部分,IL-1家族成员的表达量会显著增加,对抗微生物的入侵。例如,当TLR受体识别外来病原后,通过特定的信号通路最终将激活IL-1家族成员的大量表达。csIL-1βcDNA全长,包括5’UTR 130 bp,3’UTR 417 bp以及编码区741 bp,其中3’UTR中包含5个不稳定基序(ATTTA)以及1个加尾信号(AATAAA)。完整的ORF编码246 aa,含有一个典型的IL-1家族特征序列,但未发现interleukin-1- converting enzyme(ICE)识别位点。同源性比较结果显示csIL-1β与大菱鲆IL-1β有64%的同源性。组织表达分析表明csIL-1β与TLR9、MyD88、IRAK4类似,也具有广泛的表达谱,在12中检测组织中都有表达,尤其是免疫相关组织表达量高;不同的是csIL-1β在性腺中表达水平较低。腹腔注射后半滑舌鳎脾脏和头肾中IL-1β的表达量开始增加,并于注射后8 h达到最高点,随后逐渐降低,于注射后48 h恢复至注射前表达水平。
Half-smooth tongue sole (Cynoglossus semilaevis) is a large flatfish species widely distributed alone the coast of China. Because of its good taste and nutrition, C. semilaevis is considered as a commercially important marine fishery resource which is being widely cultured in china. Vibrio anguillarum, a kind of Gram-negative bacterium that causes hemorrhagic septicemia in fishis, is a significant threat to commercial production in marine aquaculture. The cloning of the immune related genes and the research of immune mechanism is helpful to select strains of fish with enhanced resistance to some major diseases.
Toll-like receptors (TLRs) are considered as key sensors to trigger the host’s innate immune system and adaptive immune responses by recognizing various PAMPs and initiating signal transduction. TLR9, as a member of TLR family, mediates the recognition of unmethylated CpG dinucleotide motifs commonly found in both bacterial and viral genomes. In the current study, the TLR9 gene was isolated from one of flatfish species, C. semilaevis. In the 4588 bp genomic sequence, three exons, two introns, and 5’UTR of 23 bp and 3’UTR of 342 bp were identified. Putative amino acid sequence was 1062 residues long, including a typical conserved cytosolic Toll/interleukin-1 receptor (TIR) domain, 14 leucine-rich repeat (LRR) motifs, with greater than 60% identity to gilthead sea bream Sparus aurata and Japanese flounder Paralichthys olivaceus orthologs. Quantitative RT-PCR analysis indicated a broad expression of csTLR9, especially in spleen and gonads. No statistically significant changes were observed for csTLR9 mRNA levels in spleen and head kidney after inactive V. anguillarum immunisation. In C. semilaevis ontogeny, the expression of csTLR9 appeared to be developmentally regulated. The presence of maternal TLR9 mRNA and the dramatic decrease of TLR9 expression at metamorphic stage indicated TLR9 might be involved in C. semilaevis development. Comparing sequence and expression profile of csTLR9 with mammalian and other piscine TLR9s suggested that the main function of TLR9 might be conserved across vertebrates, although species-specific features were present.
Myeloid differentiation factor 88 (MyD88) is a universal and crucial adaptor protein, which plays an essential role in the intracellular signaling elicited by IL-1R/TLR superfamily. In the present study, we report the full-length sequence of MyD88 gene in C. semilaevis. In the 2855 bp genomic sequence, five exons and four introns were identified. The cloned cDNA exhibited 110 bp of 5’UTR, 576 bp of 3’UTR and 858 bp of the entire open reading frame encoding a polypeptide of 285 amino acids. The protein sequence included a typical conserved cytosolic Toll/interleukin-1 receptor (TIR) domain, an intermediate domain (ID) and a death domain (DD), and shared greater than 70% identity with Japanese flounder P. olivaceu ortholog. RT-PCR analysis indicated a broad expression of csMyD88, especially in ovary and spleen. Quantitative RT-PCR analysis indicated that the csMyD88 mRNA levels were significantly increased in the spleen and head kidney after inactive V. anguillarum challenge and the expression of csMyD88 appeared to be developmentally regulated during C. semilaevis ontogeny. Although, species-specific differences were present, the similarity between mammalian and piscine MyD88s suggested that the main function of MyD88 might be conserved across vertebrates.
IL-1 receptor-associated kinases (IRAKs) are important mediators in the signal transduction of IL-1R/TLR superfamily members. IRAK4 is able to phosphorylate IRAK1, and overexpression of dominant-negative IRAK4 is blocking the IL-1-induced activation and modification of IRAK1, suggesting a role of IRAK4 as a central element in the early signal transduction of IL-1R/TLR receptors, upstream of IRAK1. The IRAK4 cDNA encodes a protein with 466 amino acids and a calculated molecular mass of 52 kDa. Analysis of the deduced protein sequence revealed an N-terminal death domain and a central kinase domain (S_TKc domain). The overall sequence identity shared between csIRAK4 and other fish orthologs is low, between 40-50%. A broader analysis of a tissue cDNA panel by RT-PCR revealed different level of expressions in a wide variety of tissues. The strongest expression level was observed in spleen、fin、head kidney and gonads samples. The maternal mRNA of IRAK4 in unfertilised eggs and the dramatic decrease of IRAK4 expression level during metamorphosis suggested the important role of IRAK4 in C. semilaevis development.
Interleukin-1 (IL-1) is a pleiotropic paracrine and endocrine signaling molecule and is produced by a variety of cell types. The major functions of IL-1βare activation of the proliferation of such lymphocytes as T cells and B cells, activation of cytotoxic activity in macrophage and natural killer (NK) cells, and induction of immunoglobulin (Ig) secretion. The full-length cDNA sequence of IL-1βfrom the C. semilaevis was determined by using PCR with primers designed from known fish IL-1βsequences followed by elongation of the 5’and 3’ends using RACE. The cDNA contains 130 bp 5’UTR, a single ORF of 741 bp that translates into a 247 aa molecule, 417 bp 3’UTR with five cytokine RNA instability motifs (ATTTA), and a polyadenylation signal (AATAAA) at 15 nucleotides upstream of the poly(A) tail. The deduced aa of csIL-1βshowed the highest identity (64%) with Scophthalmus maximus IL-1β. csIL-1βgene was strongly expressed in spleen, fin and head kidney and weakly expressed in muscle. After stimulation with V. anguillarum, we found a significantly increased level of IL-1βexpression in head kidney and spleen compared to that of blank control. In the head kidney and spleen of C. semilaevis stimulated by inactive V. anguillarum showed a peak level of IL-1βexpression at 8 h after intraperitoneal injection, and recovered at 48 h.
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