鱼类IL-1R及相关家族成员的分子克隆与功能研究
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摘要
IL-1R是TIR超家族成员,在IL-1、LPS介导的NF-kB信号通路中发挥重要作用。本文利用生物信息学和分子克隆等技术从模式鱼类中鉴定出鱼类IL-1RI、 DIGIRR、SIGIRR基因,并对它们的蛋白结构、遗传进化及免疫学功能进行了研究。
论文第一部分首次从Tetraodon nigroviridis鉴定出IL-1RI受体、对其基因结构、蛋白特征、组织分布、基因功能等进行了初步研究。构建原核表达质粒,纯化IL-1RI蛋白、制备了多克隆抗体。ELISA实验证明IL-1RI胞外区三个免疫球蛋白能够结合配体分子IL-1β,与IL-1RI、IL-1协同进化的计算结果相对应。而且抗体封闭IL-1RI后,IL-1介导的免疫反应被显著抑制。论文第二部分首次从模式鱼类Tetraodon nigroviridis、Gasterosteus aculeatus、Takifugu rubripe、 Oryzias latipes中鉴定出DIGIRR基因,是IL-1R/TLR家族的一个新成员。与其它IL-1R受体不同的是,DIGIRR具有两个免疫球蛋白、一个Arg-Tyr突变的TIR结构域、以及高尔基体亚细胞定位的特征。LPS刺激后,DIGIRR的mRNA表达量显著升高。体外实验表明,DIGIRR能够显著抑制IL-1β、LPS介导的NF-kB信号。而且体内DIGIRR被siRNA抑制后,IL-1β诱导的炎症因子表达量显著上调,这些数据充分证明了DIGIRR在IL-1、LPS介导的炎症信号通路中是一个负调节因子。论文第三部分首次鉴定出鱼类SIGIRR分子,蛋白结构分析、基因功能实验等方面都证实了克隆得到的受体分子是哺乳动物SIGIRR的同系物,斑马鱼SIGIRR能够抑制IL-1、LPS、CpG介导的NF-kB信号通路。
在进化上,本文提出一个IL-1RI、DIGIRR、SIGIRR起源与进化的假说,DIGIRR是SIGIRR、IL-1RI之间过渡类型的分子。DIGIRR、SIGIRR起源于同一个祖先分子IL-1R,经过两次基因复制事件,祖先分子IL-1R演化成了DIGIRR,随着世系分离,一部分物种保留了DIGIRR,而其它物种的DIGIRR进化成了SIGIRR。鱼类IL-1RI、DIGIRR、SIGIRR的鉴定证实了低等脊椎动物鱼类IL-1R/TLR调控机制的存在,有助于更好地理解IL-1R/TLR调控网络的进化历程,为鱼类免疫、病害防治工作提供了有利资料和科学依据。
Interleukin-1receptors belong to the TIR (IL-1R/TLR) superfamily members that play crucial roles in IL-1-and LPS-mediated NF-κB signaling pathways. In this study, IL-1RI, DIGIRR and SIGIRR were predicted and isolated from teleosts by bioinformatics and molecular cloning. Moreover, the protein characterization, molecular evolution and immune functions were further studied.
In part one, IL-1RI was first cloned from Tetraodon nigroviridis, and then we performed analysis of gene structures, protein characterization, mRNA distribution and gene functions. Recombinant protein of IL-1RI was successfully purified and obtained by prokaryotic expression system, and whereafter the polyclonal antibody was preapared based on the purified IL-1RI. The data showed that IL-1R receptor had affinities with its ligands IL-1β in a dose-dependent manner by ELISA, in agreement with the results of co-evolution relationship between IL-1RI and IL-1. Moreover, when IL-1RI was blocked by the anti-IL-1RI antibodies, the relative gene expression level of IL-1β-incued inflamatory factors were significant reduced.
In part two, we report a novel double-Ig-IL-1R related molecule (DIGIRR) from four model fish(Tetraodon nigroviridis, Gasterosteus aculeatus, Takifugu rubripes and Oryzias latipes), adding a previously unknown homologue to the TLR-IL-1R family. This DIGIRR molecule contains two Ig-like domains in the extracellular region, one Arg-Tyr-mutated TIR domain in the intracellular region, and a unique subcellular localization within the Golgi apparatus. These characteristics distinguish DIGIRR from other known family members. The expression of DIGIRR was significantly induced by LPS-stimulation. In vitro injection of DIGIRR into zebrafish embryos dramatically inhibited LPS-and IL-1β-induced NF-κB activation. Moreover, in vivo knockdown of DIGIRR by siRNA significantly promoted the expression of IL-1β-stimulated pro-inflammatory cytokines (IL-6and IL-1β) in DIGIRR-silenced liver and kidney tissues, and in leucocytes. These results strongly suggest that DIGIRR is an important negative regulator of LPS-and IL-1β-mediated signaling pathways and inflammatory responses.
In part three, SIGIRR was first isolated from teleost zebrafish, which is considered as the homologue of mammalians SIGIRR according to the analysis of protein characterizations and the results of gene functions. Zebrafish SIGIRR was able to inhibit IL-1β-,LPS-and CpG-indued NF-kB signaling pathways.
Evolutionally, we propose a hypothesis that DIGIRR might be an evolutionary "transitional molecule" between IL-1R and SIGIRR, representing a shift from a potent receptor to a negative regulator. These three molecules probably originated from a common ancient IL-1R-like molecule. Following two rounds of genome dulplications, ancient IL-1R-like molecule evolved into DIGIRR. With lineage divergence, parts of specieses retained DIGIRR, and meanwhile DIGIRR became SIGIRR in the other specieses.
The identifications of IL-1RI, DIGIRR and SIGIRR demonstrat that there exsit the regulation mechanisms of IL-1R/TLR signal pathways in teleosts. All data not only contribute to better understand the evolutionary history of NF-kB signaling patyways, but also provide available data and scientific evidence for host immune and disease control in fish.
论文第一部分首次从Tetraodon nigroviridis鉴定出IL-1RI受体、对其基因结构、蛋白特征、组织分布、基因功能等进行了初步研究。构建原核表达质粒,纯化IL-1RI蛋白、制备了多克隆抗体。ELISA实验证明IL-1RI胞外区三个免疫球蛋白能够结合配体分子IL-1β,与IL-1RI、IL-1协同进化的计算结果相对应。而且抗体封闭IL-1RI后,IL-1介导的免疫反应被显著抑制。论文第二部分首次从模式鱼类Tetraodon nigroviridis、Gasterosteus aculeatus、Takifugu rubripe、 Oryzias latipes中鉴定出DIGIRR基因,是IL-1R/TLR家族的一个新成员。与其它IL-1R受体不同的是,DIGIRR具有两个免疫球蛋白、一个Arg-Tyr突变的TIR结构域、以及高尔基体亚细胞定位的特征。LPS刺激后,DIGIRR的mRNA表达量显著升高。体外实验表明,DIGIRR能够显著抑制IL-1β、LPS介导的NF-kB信号。而且体内DIGIRR被siRNA抑制后,IL-1β诱导的炎症因子表达量显著上调,这些数据充分证明了DIGIRR在IL-1、LPS介导的炎症信号通路中是一个负调节因子。论文第三部分首次鉴定出鱼类SIGIRR分子,蛋白结构分析、基因功能实验等方面都证实了克隆得到的受体分子是哺乳动物SIGIRR的同系物,斑马鱼SIGIRR能够抑制IL-1、LPS、CpG介导的NF-kB信号通路。
在进化上,本文提出一个IL-1RI、DIGIRR、SIGIRR起源与进化的假说,DIGIRR是SIGIRR、IL-1RI之间过渡类型的分子。DIGIRR、SIGIRR起源于同一个祖先分子IL-1R,经过两次基因复制事件,祖先分子IL-1R演化成了DIGIRR,随着世系分离,一部分物种保留了DIGIRR,而其它物种的DIGIRR进化成了SIGIRR。鱼类IL-1RI、DIGIRR、SIGIRR的鉴定证实了低等脊椎动物鱼类IL-1R/TLR调控机制的存在,有助于更好地理解IL-1R/TLR调控网络的进化历程,为鱼类免疫、病害防治工作提供了有利资料和科学依据。
Interleukin-1receptors belong to the TIR (IL-1R/TLR) superfamily members that play crucial roles in IL-1-and LPS-mediated NF-κB signaling pathways. In this study, IL-1RI, DIGIRR and SIGIRR were predicted and isolated from teleosts by bioinformatics and molecular cloning. Moreover, the protein characterization, molecular evolution and immune functions were further studied.
In part one, IL-1RI was first cloned from Tetraodon nigroviridis, and then we performed analysis of gene structures, protein characterization, mRNA distribution and gene functions. Recombinant protein of IL-1RI was successfully purified and obtained by prokaryotic expression system, and whereafter the polyclonal antibody was preapared based on the purified IL-1RI. The data showed that IL-1R receptor had affinities with its ligands IL-1β in a dose-dependent manner by ELISA, in agreement with the results of co-evolution relationship between IL-1RI and IL-1. Moreover, when IL-1RI was blocked by the anti-IL-1RI antibodies, the relative gene expression level of IL-1β-incued inflamatory factors were significant reduced.
In part two, we report a novel double-Ig-IL-1R related molecule (DIGIRR) from four model fish(Tetraodon nigroviridis, Gasterosteus aculeatus, Takifugu rubripes and Oryzias latipes), adding a previously unknown homologue to the TLR-IL-1R family. This DIGIRR molecule contains two Ig-like domains in the extracellular region, one Arg-Tyr-mutated TIR domain in the intracellular region, and a unique subcellular localization within the Golgi apparatus. These characteristics distinguish DIGIRR from other known family members. The expression of DIGIRR was significantly induced by LPS-stimulation. In vitro injection of DIGIRR into zebrafish embryos dramatically inhibited LPS-and IL-1β-induced NF-κB activation. Moreover, in vivo knockdown of DIGIRR by siRNA significantly promoted the expression of IL-1β-stimulated pro-inflammatory cytokines (IL-6and IL-1β) in DIGIRR-silenced liver and kidney tissues, and in leucocytes. These results strongly suggest that DIGIRR is an important negative regulator of LPS-and IL-1β-mediated signaling pathways and inflammatory responses.
In part three, SIGIRR was first isolated from teleost zebrafish, which is considered as the homologue of mammalians SIGIRR according to the analysis of protein characterizations and the results of gene functions. Zebrafish SIGIRR was able to inhibit IL-1β-,LPS-and CpG-indued NF-kB signaling pathways.
Evolutionally, we propose a hypothesis that DIGIRR might be an evolutionary "transitional molecule" between IL-1R and SIGIRR, representing a shift from a potent receptor to a negative regulator. These three molecules probably originated from a common ancient IL-1R-like molecule. Following two rounds of genome dulplications, ancient IL-1R-like molecule evolved into DIGIRR. With lineage divergence, parts of specieses retained DIGIRR, and meanwhile DIGIRR became SIGIRR in the other specieses.
The identifications of IL-1RI, DIGIRR and SIGIRR demonstrat that there exsit the regulation mechanisms of IL-1R/TLR signal pathways in teleosts. All data not only contribute to better understand the evolutionary history of NF-kB signaling patyways, but also provide available data and scientific evidence for host immune and disease control in fish.
引文
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