调控抗病毒天然免疫的miRNA筛选及其作用机制研究
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摘要
天然免疫系统是宿主抵抗病原微生物的第一道防线,也是获得性免疫的基础。干扰素信号通路作为机体抵抗病毒感染所作出的重要应答机制,一直是病毒学和免疫学领域的研究热点。miRNA作为一种转录后水平的基因调控机制,广泛参与时序发育、神经元发育、细胞凋亡、细胞分化、脂肪代谢、激素分泌等多种生命过程。近年来的研究发现,miRNA在天然免疫系统中也发挥着重要的负反馈调控功能。本研究选择了抗病毒天然免疫信号通路中的几个关键信号分子作为对象,希望通过发掘靶向这些关键基因的miRNA,加深对miRNA参与的负调控机制的认识。为今后miRNA的功能研究和开发miRNA作为疾病诊断和治疗的靶标提供理论依据。具体研究内容包括以下几方面：
1.筛选poly (d AT:d AT)诱导的差异表达miRNA及其功能研究
dsRNA/DNA、细菌的内毒素脂多糖和细菌的鞭毛可以被宿主的免疫系统的模式识别受体识别并触发免疫反应。LPS和dsRNA触发的免疫反应所引起的miRNA差异表达及这些miRNA在免疫反应过程中的功能已经被发现和确定。但是,作为病毒在感染侵入宿主细胞复制过程中产生的中间产物,dsDNA刺激诱导的miRNA的差异表达研究尚不清楚。为了筛选dsDNA诱导的显著差异表达的miRNA,本研究选用dsDNA的模拟物poly(dAT:dAT)作为刺激物,通过：miRNA芯片技术,筛选了poly(dAT:dAT)刺激HEK-293细胞后差异表达的miRNA。发现miR-518b,miR-492,miR-181a和miR-331-3p等10条miRNA的表达显著上调；miR-383,miR-618,let-7a等5条miRNA的表达显著下调。利用miRNA特异性Real-Time PCR验证了芯片结果。通过靶基因预测和荧光素酶报告系统验证,发现其中上调表达的miR-181a可能通过靶向DAI基因负性调节干扰素信号通路。2.筛选调控IL-6基因表达的]miRNA及其机制研究
白细胞介素6(IL-6)是一种重要的炎性细胞因子。细胞在受到致炎性刺激时,IL-6的表达量显著上调,并促进其它炎性细胞因子或者趋化因子的分泌,从而加重炎症反应,加速外源异物的清除。但是IL-6表达的紊乱对机体是有损害的,过量的IL-6会导致持续的炎症,并可能最终导致持续炎症组织发生癌变。因此,维持IL-6正常表达的负调控机制就显得至关重要。据此,本研究利用生物信息学方法,预测可能结合于IL-63’UTR区域的miRNA。利用荧光素酶报告系统,筛选到负调控IL-6表达的miR-365。通过构建IL-63’UTR突变体的报告质粒,确定了miR-365结合于IL-63’UTR的精细位点。利用ELISA方法,证实miR-365可以从蛋白水平对IL-6进行负调控,而且这种负调控是通过抑制IL-6蛋白的翻译而不是影响其mRNA的稳定性来实现的。对miR-365启动子区域的分析,发现NF-KB和Spl两个转录因子协同调控miR-365的转录。利用MAPK/ERK的抑制剂发现MAPK/ERK是miR-365上游重要的信号通路。进-步对miR-365潜在靶基因进行分析,发现miR-365还可能通过间接途径调控IL-6的表达。
3.筛选靶向TBK-1的miRNA及其机制研究
TBK-1是Ⅰ型干扰素信号通路中的重要信号分子,主要功能是磷酸化转录因子IRF3和IRF7,促进它们的转定位并最终启始IFN-p的转录。TLR或RIG-I/MDA5依赖的抗病毒信号通路在TBK-1/IRF3节段交汇,充分说明TBK-1激酶在整个抗病毒免疫系统中不可替代的重要性。为了发掘可能通过靶向TBK-1负调控干扰素信号通路的miRNA,本研究通过生物信息学预测miR-155可能靶向TBK-1,利用TBK-1-3’UTR的报告质粒证实了miR-155对TBK-1表达的抑制作用；过表达miR-155显著抑制TBK-1蛋白的表达,而miR-155抑制剂则增强TBK-1蛋白的表达,进一步证实了miR-155对TBK-1表达的负调控作用。利用TBK-13’UTR的突变体报告质粒,确定了miR-155与TBK-13’UTR区域的精确结合位点。在证实miR-155对TBK-1的负调控作用后,进一步利用IRF3、NF-κB和IFN-β的启动子荧光素报告质粒,证实miR-155过表达显著抑制IRF3和NF-κB的活性,并最终抑制IFN-β的转录。对TBK-1的Knockdown和Gain-of function assay的实验结果也证实miR-155负调控干扰素信号通路是通过靶向TBK-1而实现的。为了进一步证实miR-155对干扰素表达的抑制作用,检测了miR-155过表达对VSV和SEV增殖的影响,发现miR-155可通过抑制1poly(dAT:dAT)诱导的干扰素表达而促进VSV和SEV在HEK-293中的增殖。研究还发现poly(dAT:dAT)刺激显著诱导miR-155的表达,且NF-KB和MAPK是调控miR-155表达的重要通路。这些结果表明,可诱导的miR-155的表达在Ⅰ型干扰素信号通路中扮演着重要的负调控机制。4.筛选靶向JAK-1的miRNA及其机制研究
JAK-STAT信号通路是连接干扰素和下游干扰素刺激基因的重要信号通路。JAK-1是Janus非受体型络氨酸激酶家族的成员之一。干扰素与细胞表面受体结合后,JAK-1磷酸化STAT家族中的两个成员STAT-1和STAT-2,促使其发生向细胞核的转定位并诱导干扰素刺激基因的转录激活。除干扰素之外,JAK-1在IL-2,IL-4,IL-6,IL-10,IL-13等细胞因子的信号转导通路中也发挥重要功能。到目前为止,还没有关于miRNA调控JAK-1表达的报道。为了发掘靶向JAK-1的miRNA,本研究预测并证实miR-23a通过直接与3’UTR结合的方式负调控JAK-1基因的表达。通过结合位点的突变分析,确定了miR-23a和JAK-1相互作用的精细位点。同时,发现miR-23a过表达显著抑制JAK-1的蛋白表达,且主要是通过降低mRNA的稳定性来实现的。过表达miR-23a对ISRE的活性及下游ISG的表达也有明显的抑制效应。用poly(dAT:dAT)刺激细胞,发现miR-23a的表达在刺激晚期显著上调,且NF-κB和MAPK/JNK信号通路可能是miR-23a上游的重要信号通路。这些结果表明,miR-23a可能在JAK-STAT信号通路中扮演着负反馈调控机制,以确保整条通路处于适度激活的状态。
The innate immunity is the first line to defense against invading pathogens and is also essential for the subsequent adaptive immune response. The interferon signaling represents the key aspect of the anti-viral immunity. Thus, the studies focused on the type I interferon have been the hot issues in both virology and immunology fields. As one of the post-transcriptional gene regulatory mechanism, miRNA was involved in a wide range of life processes which include development, neuron development, apoptosis, proliferation, fat metabolism and hormone secretion. In the recent years, growing evidences have demonstrated that miRNA plays a negative regulatory role in the innate immunity. The present study tries to discover novel miRNAs who regulate the expression of several key signal molecules in the anti-viral signaling. With this effort, we try to deepen the understanding of the miRNA based negative regulatory mechanism. This study will provide theoretical basis for the future miRNA study and the development of miRNA as a potential target for disease diagnosis and therapy. The detailed research includes the following aspects:
1. Screening for dsDNA-induced differently expressed miRNA and function study.
dsRNA, dsDNA, LPS and flagellin were recognized by the cell surface PRRs and trigger the cellular innate immunity. LPS and dsRNA induced differential miRNA expression have been well characterized. As the bypass products of viral replication in the host cells, dsDNA induced differently expressed miRNA remains largely unknown. Thus, we use miRNA microarray to screen for the differently expressed miRNAs in response to the dsDNA mimic poly(dAT:dAT) stimulation. We found ten up-rugulated miRNAs which include miR-518b, miR-492, miR-181a and miR-331-3p; five down-regulated miRNA which include miR-383, miR-618and let-7a. We utilized the miRNA specific Real-Time PCR to validate the result. Furthermore, we predicted miRNAs'targets and made validation by using luciferase repoter system. We found that miR-181a negatively regulate the interferon signaling by targeting receptor DAI.
2. Screening for the miRNA who regulate IL-6expression and mechanism study
Interleukin-6(IL-6) is a pleiotropic cytokine. Upon inflammatory stimulation, the IL-6expression was highly induced and promotes other pro-inflammatory cytokines and chemokines secretion. The induced IL-6expression will intensify the inflammation to eliminate the pathogens rapidly. However, the uncontrolled IL-6expression is harmful to body health. The sustained inflammation plays an important role in the carcinogenesis. Thus, the negative regulatory mechanism to make sure the appropriate IL-6expression is indispensable to the body health. We used a bioinformatics technique to predict miRNA targeting IL-6. We found miR-365negatively regulate IL-6expression by using luciferase gene reporter system. Mutagenesis analysis revealed the precise binding site for miR-365in TBK-1's3'UTR region. ELISA assay demonstrated that miR-365negatively regulate IL-6protein expression. Real-Time PCR showed that miR-365repress the expresson of IL-6without decreasing its mRNA stability. Analysis of the miR-365promoter showed that two transcription factors, Spl and NF-κB, cooperatively regulate the transcription of miR-365. We also demonstrate that the MAPK/ERK pathway contributes to the regulation of miR-365by using specific inhibitor. Furthermore, after analysis of potential targets of miR-365, we found that it is possible that miR-365can also regulate IL-6exprssion indirectly.
3. Screening for the miRNA who regulate TBK-1expression and mechanism study
TBK-1is the key signal molecule in the type I interferon signaling pathway. Its primary function is the phosphorylation of transcription factor IRF3and IRF7which lead their translocation into nucleus and the initiation of IFN-β transcription. TLR-and RIG-I-dependent anti-viral signaling converges at TBK-1-IRF3model emphasizes TBK-1's essential role in the anti-viral immunity. In order to discover potential miRNA which negatively regulate interferon signaling by targeting TBK-1, we predicted miRNAs which target TBK-1mRNA. We found miR-155out of the candidates inhibited reporter gene's expression. Ectopic expression of miR-155significantly repressed TBK-1protein expression. In contrast, miR-155inhibitor increased TBK-1protein expression. Both of the results demonstrated that miR-155negatively regulate TBK-1expression. Mutagenesis analysis revealed the precise binding site for miR-155in the TBK-1's3'UTR region. Furthermore, ectopic expression of miR-155decreased IRF3and NF-κB activity, which in turn blocked IFN-β transcription. TBK-1knockdown and gain-of function assay demonstrated that miR-155's inhibitory effect is achieved through blocking TBK-1expression.In order to evaluate the effect of miR-155on poly(dAT:dAT) induced interferon expression, we determined the miR-155's effect on VSV or SEV replication. We found that ectopic expression of miR-155promoted VSV and SEV replication in HEK-293by blocking interferon secretion. We also found that miR-155was induced by inflammatory stimulation. NF-κB and MAPK signaling are highly involved in the transcriptional regulation of miR-155. Our data showed that the inducible expression of miR-155may represent an important negative feedback regulation of interferon signaling pathway.
4. Screening for the miRNA who regulate JAK-1expression and mechanism study
JAK-STAT is one of the most important signaling which links interferon and interferon stimulating genes. JAK-1is a member of Janus non-receptor tyrosine kinas family. When interferons binding to its receptor in the cell surface. JAK-1phosphorylates STAT-1and STAT-2, two members of STAT family. Subsequently, they translocate from cytoplasm into nucleus and initiate the transcription of interferon stimulation genes. JAK-1also plays an important role in the cytokine signaling which include IL-2, IL-4, IL-6, IL-10and IL-13. Untill now, no miRNA was indentified as the regulator of JAK-1. In order to discover miRNA which target JAK-1, we screened and identified miR-23a as a novel regulator of JAK-1gene by binding to its3'UTR. Site-direct mutagenesis assay identified the precise binding region for miR-23a. Western-blot assay indicated that miR-23a could significantly repress the JAK-1protein expression and this is mainly through degrading JAK-1mRNA. Luciferase reporter gene based assay and Real-Time PCR result showed that miR-23a could inhibit interferon induced ISRE activity and interferon-stimulating gene expression. Our data also showed that miR-23a could be induced in the late phase after the immuno-stimulation. Pharmacological inhibitor assay showed that NF-κB and MAPK/JNK is involved in the transcriptional regulation of miR-23a. Our study indicated that the inducible miR-23a in response to interferon provides a negative feedback mechanism to keep the proper activity of JAK-STAT signaling.
1.筛选poly (d AT:d AT)诱导的差异表达miRNA及其功能研究
dsRNA/DNA、细菌的内毒素脂多糖和细菌的鞭毛可以被宿主的免疫系统的模式识别受体识别并触发免疫反应。LPS和dsRNA触发的免疫反应所引起的miRNA差异表达及这些miRNA在免疫反应过程中的功能已经被发现和确定。但是,作为病毒在感染侵入宿主细胞复制过程中产生的中间产物,dsDNA刺激诱导的miRNA的差异表达研究尚不清楚。为了筛选dsDNA诱导的显著差异表达的miRNA,本研究选用dsDNA的模拟物poly(dAT:dAT)作为刺激物,通过：miRNA芯片技术,筛选了poly(dAT:dAT)刺激HEK-293细胞后差异表达的miRNA。发现miR-518b,miR-492,miR-181a和miR-331-3p等10条miRNA的表达显著上调；miR-383,miR-618,let-7a等5条miRNA的表达显著下调。利用miRNA特异性Real-Time PCR验证了芯片结果。通过靶基因预测和荧光素酶报告系统验证,发现其中上调表达的miR-181a可能通过靶向DAI基因负性调节干扰素信号通路。2.筛选调控IL-6基因表达的]miRNA及其机制研究
白细胞介素6(IL-6)是一种重要的炎性细胞因子。细胞在受到致炎性刺激时,IL-6的表达量显著上调,并促进其它炎性细胞因子或者趋化因子的分泌,从而加重炎症反应,加速外源异物的清除。但是IL-6表达的紊乱对机体是有损害的,过量的IL-6会导致持续的炎症,并可能最终导致持续炎症组织发生癌变。因此,维持IL-6正常表达的负调控机制就显得至关重要。据此,本研究利用生物信息学方法,预测可能结合于IL-63’UTR区域的miRNA。利用荧光素酶报告系统,筛选到负调控IL-6表达的miR-365。通过构建IL-63’UTR突变体的报告质粒,确定了miR-365结合于IL-63’UTR的精细位点。利用ELISA方法,证实miR-365可以从蛋白水平对IL-6进行负调控,而且这种负调控是通过抑制IL-6蛋白的翻译而不是影响其mRNA的稳定性来实现的。对miR-365启动子区域的分析,发现NF-KB和Spl两个转录因子协同调控miR-365的转录。利用MAPK/ERK的抑制剂发现MAPK/ERK是miR-365上游重要的信号通路。进-步对miR-365潜在靶基因进行分析,发现miR-365还可能通过间接途径调控IL-6的表达。
3.筛选靶向TBK-1的miRNA及其机制研究
TBK-1是Ⅰ型干扰素信号通路中的重要信号分子,主要功能是磷酸化转录因子IRF3和IRF7,促进它们的转定位并最终启始IFN-p的转录。TLR或RIG-I/MDA5依赖的抗病毒信号通路在TBK-1/IRF3节段交汇,充分说明TBK-1激酶在整个抗病毒免疫系统中不可替代的重要性。为了发掘可能通过靶向TBK-1负调控干扰素信号通路的miRNA,本研究通过生物信息学预测miR-155可能靶向TBK-1,利用TBK-1-3’UTR的报告质粒证实了miR-155对TBK-1表达的抑制作用；过表达miR-155显著抑制TBK-1蛋白的表达,而miR-155抑制剂则增强TBK-1蛋白的表达,进一步证实了miR-155对TBK-1表达的负调控作用。利用TBK-13’UTR的突变体报告质粒,确定了miR-155与TBK-13’UTR区域的精确结合位点。在证实miR-155对TBK-1的负调控作用后,进一步利用IRF3、NF-κB和IFN-β的启动子荧光素报告质粒,证实miR-155过表达显著抑制IRF3和NF-κB的活性,并最终抑制IFN-β的转录。对TBK-1的Knockdown和Gain-of function assay的实验结果也证实miR-155负调控干扰素信号通路是通过靶向TBK-1而实现的。为了进一步证实miR-155对干扰素表达的抑制作用,检测了miR-155过表达对VSV和SEV增殖的影响,发现miR-155可通过抑制1poly(dAT:dAT)诱导的干扰素表达而促进VSV和SEV在HEK-293中的增殖。研究还发现poly(dAT:dAT)刺激显著诱导miR-155的表达,且NF-KB和MAPK是调控miR-155表达的重要通路。这些结果表明,可诱导的miR-155的表达在Ⅰ型干扰素信号通路中扮演着重要的负调控机制。4.筛选靶向JAK-1的miRNA及其机制研究
JAK-STAT信号通路是连接干扰素和下游干扰素刺激基因的重要信号通路。JAK-1是Janus非受体型络氨酸激酶家族的成员之一。干扰素与细胞表面受体结合后,JAK-1磷酸化STAT家族中的两个成员STAT-1和STAT-2,促使其发生向细胞核的转定位并诱导干扰素刺激基因的转录激活。除干扰素之外,JAK-1在IL-2,IL-4,IL-6,IL-10,IL-13等细胞因子的信号转导通路中也发挥重要功能。到目前为止,还没有关于miRNA调控JAK-1表达的报道。为了发掘靶向JAK-1的miRNA,本研究预测并证实miR-23a通过直接与3’UTR结合的方式负调控JAK-1基因的表达。通过结合位点的突变分析,确定了miR-23a和JAK-1相互作用的精细位点。同时,发现miR-23a过表达显著抑制JAK-1的蛋白表达,且主要是通过降低mRNA的稳定性来实现的。过表达miR-23a对ISRE的活性及下游ISG的表达也有明显的抑制效应。用poly(dAT:dAT)刺激细胞,发现miR-23a的表达在刺激晚期显著上调,且NF-κB和MAPK/JNK信号通路可能是miR-23a上游的重要信号通路。这些结果表明,miR-23a可能在JAK-STAT信号通路中扮演着负反馈调控机制,以确保整条通路处于适度激活的状态。
The innate immunity is the first line to defense against invading pathogens and is also essential for the subsequent adaptive immune response. The interferon signaling represents the key aspect of the anti-viral immunity. Thus, the studies focused on the type I interferon have been the hot issues in both virology and immunology fields. As one of the post-transcriptional gene regulatory mechanism, miRNA was involved in a wide range of life processes which include development, neuron development, apoptosis, proliferation, fat metabolism and hormone secretion. In the recent years, growing evidences have demonstrated that miRNA plays a negative regulatory role in the innate immunity. The present study tries to discover novel miRNAs who regulate the expression of several key signal molecules in the anti-viral signaling. With this effort, we try to deepen the understanding of the miRNA based negative regulatory mechanism. This study will provide theoretical basis for the future miRNA study and the development of miRNA as a potential target for disease diagnosis and therapy. The detailed research includes the following aspects:
1. Screening for dsDNA-induced differently expressed miRNA and function study.
dsRNA, dsDNA, LPS and flagellin were recognized by the cell surface PRRs and trigger the cellular innate immunity. LPS and dsRNA induced differential miRNA expression have been well characterized. As the bypass products of viral replication in the host cells, dsDNA induced differently expressed miRNA remains largely unknown. Thus, we use miRNA microarray to screen for the differently expressed miRNAs in response to the dsDNA mimic poly(dAT:dAT) stimulation. We found ten up-rugulated miRNAs which include miR-518b, miR-492, miR-181a and miR-331-3p; five down-regulated miRNA which include miR-383, miR-618and let-7a. We utilized the miRNA specific Real-Time PCR to validate the result. Furthermore, we predicted miRNAs'targets and made validation by using luciferase repoter system. We found that miR-181a negatively regulate the interferon signaling by targeting receptor DAI.
2. Screening for the miRNA who regulate IL-6expression and mechanism study
Interleukin-6(IL-6) is a pleiotropic cytokine. Upon inflammatory stimulation, the IL-6expression was highly induced and promotes other pro-inflammatory cytokines and chemokines secretion. The induced IL-6expression will intensify the inflammation to eliminate the pathogens rapidly. However, the uncontrolled IL-6expression is harmful to body health. The sustained inflammation plays an important role in the carcinogenesis. Thus, the negative regulatory mechanism to make sure the appropriate IL-6expression is indispensable to the body health. We used a bioinformatics technique to predict miRNA targeting IL-6. We found miR-365negatively regulate IL-6expression by using luciferase gene reporter system. Mutagenesis analysis revealed the precise binding site for miR-365in TBK-1's3'UTR region. ELISA assay demonstrated that miR-365negatively regulate IL-6protein expression. Real-Time PCR showed that miR-365repress the expresson of IL-6without decreasing its mRNA stability. Analysis of the miR-365promoter showed that two transcription factors, Spl and NF-κB, cooperatively regulate the transcription of miR-365. We also demonstrate that the MAPK/ERK pathway contributes to the regulation of miR-365by using specific inhibitor. Furthermore, after analysis of potential targets of miR-365, we found that it is possible that miR-365can also regulate IL-6exprssion indirectly.
3. Screening for the miRNA who regulate TBK-1expression and mechanism study
TBK-1is the key signal molecule in the type I interferon signaling pathway. Its primary function is the phosphorylation of transcription factor IRF3and IRF7which lead their translocation into nucleus and the initiation of IFN-β transcription. TLR-and RIG-I-dependent anti-viral signaling converges at TBK-1-IRF3model emphasizes TBK-1's essential role in the anti-viral immunity. In order to discover potential miRNA which negatively regulate interferon signaling by targeting TBK-1, we predicted miRNAs which target TBK-1mRNA. We found miR-155out of the candidates inhibited reporter gene's expression. Ectopic expression of miR-155significantly repressed TBK-1protein expression. In contrast, miR-155inhibitor increased TBK-1protein expression. Both of the results demonstrated that miR-155negatively regulate TBK-1expression. Mutagenesis analysis revealed the precise binding site for miR-155in the TBK-1's3'UTR region. Furthermore, ectopic expression of miR-155decreased IRF3and NF-κB activity, which in turn blocked IFN-β transcription. TBK-1knockdown and gain-of function assay demonstrated that miR-155's inhibitory effect is achieved through blocking TBK-1expression.In order to evaluate the effect of miR-155on poly(dAT:dAT) induced interferon expression, we determined the miR-155's effect on VSV or SEV replication. We found that ectopic expression of miR-155promoted VSV and SEV replication in HEK-293by blocking interferon secretion. We also found that miR-155was induced by inflammatory stimulation. NF-κB and MAPK signaling are highly involved in the transcriptional regulation of miR-155. Our data showed that the inducible expression of miR-155may represent an important negative feedback regulation of interferon signaling pathway.
4. Screening for the miRNA who regulate JAK-1expression and mechanism study
JAK-STAT is one of the most important signaling which links interferon and interferon stimulating genes. JAK-1is a member of Janus non-receptor tyrosine kinas family. When interferons binding to its receptor in the cell surface. JAK-1phosphorylates STAT-1and STAT-2, two members of STAT family. Subsequently, they translocate from cytoplasm into nucleus and initiate the transcription of interferon stimulation genes. JAK-1also plays an important role in the cytokine signaling which include IL-2, IL-4, IL-6, IL-10and IL-13. Untill now, no miRNA was indentified as the regulator of JAK-1. In order to discover miRNA which target JAK-1, we screened and identified miR-23a as a novel regulator of JAK-1gene by binding to its3'UTR. Site-direct mutagenesis assay identified the precise binding region for miR-23a. Western-blot assay indicated that miR-23a could significantly repress the JAK-1protein expression and this is mainly through degrading JAK-1mRNA. Luciferase reporter gene based assay and Real-Time PCR result showed that miR-23a could inhibit interferon induced ISRE activity and interferon-stimulating gene expression. Our data also showed that miR-23a could be induced in the late phase after the immuno-stimulation. Pharmacological inhibitor assay showed that NF-κB and MAPK/JNK is involved in the transcriptional regulation of miR-23a. Our study indicated that the inducible miR-23a in response to interferon provides a negative feedback mechanism to keep the proper activity of JAK-STAT signaling.
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