泡沫病毒转录激活因子调控宿主细胞周期并受宿主细胞microRNA的调控
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摘要
病毒是一种病原体,由于自身包装能力的限制,所以必须依赖于宿主细胞进行增殖与复制,并且对宿主细胞造成破坏。与此相反,宿主细胞在病毒进入到自身后,马上会启动其防御机制,抵抗、削弱、甚至清除病毒感染。本论文主要以泡沫病毒为研究工具,研究该类病毒对宿主细胞,特别是宿主细胞周期的抑制作用。以及宿主microRNA对病毒相关基因的调控及对病毒复制的影响。本研究还初步揭示了RNA沉默抑制因子,即番茄丛矮病毒的P19蛋白,对宿主细胞周期相关基因有显著的调控作用。
Borf1蛋白是牛泡沫病毒编码的转录激活因子,可影响其自身及病毒结构基因的表达。但目前对Borf1在宿主细胞周期上是否发挥作用还不清楚。在本研究中,我们通过构建人胚肾293稳定表达Borf1的细胞系来研究其对宿主细胞的影响。研究发现,在细胞内稳定表达Borf1可显著引发细胞在G1/G0的阻滞,并且降低S期细胞的比例。用半定量RT-PCR分析发现,Borf1可在mRNA水平下调cyclin A2,cyclin B1,cyclin E1和CDC2,及上调CDK2和E2F-1的表达。蛋白水平的分析进一步核实上述结果,并且发现Borf1还可抑制P15蛋白表达。因此,Borf1通过影响周期相关蛋白表达,在G2-M及G1-S限制位点上发挥作用,进而引发细胞G1期阻抑。
番茄丛矮病毒的P19蛋白不仅是一个重要的病毒致病因子,而且还可作为RNA干扰(RNAi)的抑制因子。这种作用是通过限制细胞内的小RNA,比如小干扰RNA(siRNAs)和microRNA(miRNAs)来实现。但是目前人们对P19蛋白是否可能对哺乳动物细胞产生不利影响还不知。在本研究中,我们构建了一株p19稳定表达的293细胞系,即293-p19。流式细胞仪分析发现在293细胞中过量表达P19蛋白可显著引发细胞周期的G2/M阻滞。细胞增殖实验显示293-p19细胞的DNA复制及细胞生长均受到显著的抑制。此外,研究还发现p19可使人胚肾293细胞内的细胞周期调控蛋白的表达谱发生改变。其中包括上调cyclin A1,CDK2,CDK4,CDK6,p27,cyclin D2,cyclin D3 and E2F1,及下调p15,cyclin A,cyclin B1和cyclin E1的表达。因此,我们的研究结果提示,p19有可能靶向多个周期相关调控蛋白从而引发细胞的G2/M阻滞。
microRNA(miRNA)是一类大小为21-25nt的非编码RNA,在转录后水平发挥基因的抑制作用。通常microRNA可通过抑制靶序列的翻译,或引发靶序列的降解来达到其负调控目的。虽然目前microRNA分子已知的很多,但真正明确其功能的却很少。另外,有关microRNA对泡沫病毒作用的研究报道也极其有限。为此,我们利用生物信息学预测软件对人泡沫病毒(HFV)基因组进行分析,发现HFV的转录激活子Bel 1(Tas)的编码区上有一个has-miR-491-5p的靶位点。将靶序列置于EGFP基因的3'非编码区(UTR),用化学合成的及载体表达的has-miR-491-5p均可显著抑制EGFP的基因表达。用化学修饰的特异性miRNA抑制剂及过量表达p19,均可有效解救has-miR-491-5p引发的基因抑制。研究还发现,has-miR-491-5p介导的基因抑制发生于转录后mRNA水平,而非蛋白质表达水平。不仅如此,has-miR-491-5p还可有效抑制Bel 1在质粒及病毒中的表达。该系统为进一步检测has-miR-491-5p抑制HFV病毒的复制奠定了基础。
总之,病毒早期感染产生的某些重要的调控蛋白如Borf1和P19,不仅可作用于病毒基因组复制本身,而且还可作用于宿主细胞周期,通过改变周期蛋白的表达来引发细胞周期的阻抑。此外,宿主细胞对病毒的侵入性感染也呈现多种防御性作用机制,其中之一就是在细胞内引发针对病毒的miRNA介导的转录后水平的基因抑制。如miR-491对HFV Bel1蛋白的抑制作用,就有可能是宿主miRNA通过限制转录激活因子的表达抑制HFV病毒的复制。miR-491介导的这种抑制作用有可能会为病毒建立潜伏感染提供有利条件。
Virus is a kind of pathogen that has to utilize cellular machinery to complete its proliferation and replication. Due to the limited package capacity, the virus could not encode all the proteins required for this process. In contrast, after viral infection, the host cell immediately initiates its defense mechanisms to counteract, reduce and even eliminate the viral invasion. In this thesis, foamy virus was used as a model system to study the interaction between this virus and the host cell, especially the impact of viral infection on host cell cycle progression. In addition, current study revealed that the RNA silencing repressor, the Tombusvirus p19 protein, regulated the expressions of cell cycle related genes in mammal cells.
Borf1 is a transcription activator encoded by bovine foamy virus genome, and can activate the transcriptions of its own gene as well as viral structural genes. However, the effect of Borf1 on the expressions of cell cycle related genes has not been exploited. In current study, a human embryonic kidney 293 cell stably expressing Borf1 gene was established and used for the detection of the effect of Borf1 on the endogenous gene expressions in host cells. The results revealed that stably expressing Borf1 significantly caused G1/G0 arrest, and in the same time reduced S phase population. Semi-quantitative RT-PCR demonstrated that Borf1 down-regulated the mRNA levels of cyclin A2, cyclin B1, cyclin E1 and CDC2, and upregulated the mRNA levels of CDK2 and E2F-1. Western blot analysis on these cell cycle related genes further confirmed the above results. Additionally, Borf1 could reduce the endogenous p15 protein expression. Thus. Borf1 may cause G1 arrest by influencing the expressions of a number of cell cycle related genes which may play critical roles at the restriction points during G2-M and G1-S transition.
Besides its function as a pathogenicity determinant, the Tombusvirus P19 also serves as a suppressor of RNA interference (RNAi) by sequestering intracellular small RNAs such as the small interfering RNAs (siRNAs) and microRNAs (miRNAs). However, the effect of P19 on mammalian cells has not been evaluated before. In this study, a human embryonic kidney 293 cell line that stably expressed p19 (HEK293-p19) was generated. Flow cytometric analysis revealed that over-expression of P19 caused a significant accumulation of G2/M phase cells. Cell proliferation assays demonstrated a reduced DNA replication and cell growth in HEK293-p19 cells. Moreover, p19 altered the expression profiles of a number of cell cycle regulators in HEK293 cells, such as upregulation of cyclin A1, CDK2, CDK4, CDK6, p27, cyclin D2, cyclin D3 and E2F1, and downregulation of p15, cyclin A2, cyclin B1 and cyclin E1. Thus, the data strongly indicate that p19 might influence multiple G2/M regulators to cause G2/M arrest.
MicroRNA is a class of noncoding RNAs with 21-25nt in length that functions posttranscriptionally to repress targeted gene expression by either inhibiting protein translation or promoting mRNA degradation. Although a large number of microRNAs have been isolated, only a few of them have the known functions. Moreover, there are only limited reports on the roles of microRNA in HFV infection. To this end, we used bioinformatic approach to screen the potential microRNA targeting site(s) in the RNA genome of human foamy virus (HFV). We found one has-miR-491-5p targeting site in the coding region of Bell gene. The targeted sequence was isolated from HFV and inserted into the 3'UTR of pEGFP-C1. The EGFP expressions were significantly repressed by either the chemically synthesized or the vector expressed has-miR-491-5p. Further, the repression could be rescued with either the chemically modified miRNA inhibitor or the overexpression of p19. Study indicated that has-miR-491-5p mediated posttranscriptionally gene repression occurred at mRNA rather than protein level. Finally, has-miR-491-5p could effectively blocked Bell expressions from both expression vector and HFV viral genome. Thus, the established system might be useful for the study of HFV replication and gene regulation.
In conclusion, some key regulatory proteins such as Borf1 and P19 produced from early viral infection have major influences on not only viral genome replication but also host cell cycle progression such as cell cycle arrest, which can be induced by the alterations of cell cycle related genes. In additoion, the host may exert its many defense mechanisms against viral invasion. One of the choices that the virus uses for self-defense might be to induce posttranscriptional gene silencing mediated by target site-specific microRNA. For example, the host miR-491 might inhibit HFV viral replication by miRNA-mediated posttranscriptional gene repression to down-regulate the expression of transcriptional activator Bell. This type of gene repression mediated by miR-491 may offer a good advantage for HFV to establish viral latency.
Borf1蛋白是牛泡沫病毒编码的转录激活因子,可影响其自身及病毒结构基因的表达。但目前对Borf1在宿主细胞周期上是否发挥作用还不清楚。在本研究中,我们通过构建人胚肾293稳定表达Borf1的细胞系来研究其对宿主细胞的影响。研究发现,在细胞内稳定表达Borf1可显著引发细胞在G1/G0的阻滞,并且降低S期细胞的比例。用半定量RT-PCR分析发现,Borf1可在mRNA水平下调cyclin A2,cyclin B1,cyclin E1和CDC2,及上调CDK2和E2F-1的表达。蛋白水平的分析进一步核实上述结果,并且发现Borf1还可抑制P15蛋白表达。因此,Borf1通过影响周期相关蛋白表达,在G2-M及G1-S限制位点上发挥作用,进而引发细胞G1期阻抑。
番茄丛矮病毒的P19蛋白不仅是一个重要的病毒致病因子,而且还可作为RNA干扰(RNAi)的抑制因子。这种作用是通过限制细胞内的小RNA,比如小干扰RNA(siRNAs)和microRNA(miRNAs)来实现。但是目前人们对P19蛋白是否可能对哺乳动物细胞产生不利影响还不知。在本研究中,我们构建了一株p19稳定表达的293细胞系,即293-p19。流式细胞仪分析发现在293细胞中过量表达P19蛋白可显著引发细胞周期的G2/M阻滞。细胞增殖实验显示293-p19细胞的DNA复制及细胞生长均受到显著的抑制。此外,研究还发现p19可使人胚肾293细胞内的细胞周期调控蛋白的表达谱发生改变。其中包括上调cyclin A1,CDK2,CDK4,CDK6,p27,cyclin D2,cyclin D3 and E2F1,及下调p15,cyclin A,cyclin B1和cyclin E1的表达。因此,我们的研究结果提示,p19有可能靶向多个周期相关调控蛋白从而引发细胞的G2/M阻滞。
microRNA(miRNA)是一类大小为21-25nt的非编码RNA,在转录后水平发挥基因的抑制作用。通常microRNA可通过抑制靶序列的翻译,或引发靶序列的降解来达到其负调控目的。虽然目前microRNA分子已知的很多,但真正明确其功能的却很少。另外,有关microRNA对泡沫病毒作用的研究报道也极其有限。为此,我们利用生物信息学预测软件对人泡沫病毒(HFV)基因组进行分析,发现HFV的转录激活子Bel 1(Tas)的编码区上有一个has-miR-491-5p的靶位点。将靶序列置于EGFP基因的3'非编码区(UTR),用化学合成的及载体表达的has-miR-491-5p均可显著抑制EGFP的基因表达。用化学修饰的特异性miRNA抑制剂及过量表达p19,均可有效解救has-miR-491-5p引发的基因抑制。研究还发现,has-miR-491-5p介导的基因抑制发生于转录后mRNA水平,而非蛋白质表达水平。不仅如此,has-miR-491-5p还可有效抑制Bel 1在质粒及病毒中的表达。该系统为进一步检测has-miR-491-5p抑制HFV病毒的复制奠定了基础。
总之,病毒早期感染产生的某些重要的调控蛋白如Borf1和P19,不仅可作用于病毒基因组复制本身,而且还可作用于宿主细胞周期,通过改变周期蛋白的表达来引发细胞周期的阻抑。此外,宿主细胞对病毒的侵入性感染也呈现多种防御性作用机制,其中之一就是在细胞内引发针对病毒的miRNA介导的转录后水平的基因抑制。如miR-491对HFV Bel1蛋白的抑制作用,就有可能是宿主miRNA通过限制转录激活因子的表达抑制HFV病毒的复制。miR-491介导的这种抑制作用有可能会为病毒建立潜伏感染提供有利条件。
Virus is a kind of pathogen that has to utilize cellular machinery to complete its proliferation and replication. Due to the limited package capacity, the virus could not encode all the proteins required for this process. In contrast, after viral infection, the host cell immediately initiates its defense mechanisms to counteract, reduce and even eliminate the viral invasion. In this thesis, foamy virus was used as a model system to study the interaction between this virus and the host cell, especially the impact of viral infection on host cell cycle progression. In addition, current study revealed that the RNA silencing repressor, the Tombusvirus p19 protein, regulated the expressions of cell cycle related genes in mammal cells.
Borf1 is a transcription activator encoded by bovine foamy virus genome, and can activate the transcriptions of its own gene as well as viral structural genes. However, the effect of Borf1 on the expressions of cell cycle related genes has not been exploited. In current study, a human embryonic kidney 293 cell stably expressing Borf1 gene was established and used for the detection of the effect of Borf1 on the endogenous gene expressions in host cells. The results revealed that stably expressing Borf1 significantly caused G1/G0 arrest, and in the same time reduced S phase population. Semi-quantitative RT-PCR demonstrated that Borf1 down-regulated the mRNA levels of cyclin A2, cyclin B1, cyclin E1 and CDC2, and upregulated the mRNA levels of CDK2 and E2F-1. Western blot analysis on these cell cycle related genes further confirmed the above results. Additionally, Borf1 could reduce the endogenous p15 protein expression. Thus. Borf1 may cause G1 arrest by influencing the expressions of a number of cell cycle related genes which may play critical roles at the restriction points during G2-M and G1-S transition.
Besides its function as a pathogenicity determinant, the Tombusvirus P19 also serves as a suppressor of RNA interference (RNAi) by sequestering intracellular small RNAs such as the small interfering RNAs (siRNAs) and microRNAs (miRNAs). However, the effect of P19 on mammalian cells has not been evaluated before. In this study, a human embryonic kidney 293 cell line that stably expressed p19 (HEK293-p19) was generated. Flow cytometric analysis revealed that over-expression of P19 caused a significant accumulation of G2/M phase cells. Cell proliferation assays demonstrated a reduced DNA replication and cell growth in HEK293-p19 cells. Moreover, p19 altered the expression profiles of a number of cell cycle regulators in HEK293 cells, such as upregulation of cyclin A1, CDK2, CDK4, CDK6, p27, cyclin D2, cyclin D3 and E2F1, and downregulation of p15, cyclin A2, cyclin B1 and cyclin E1. Thus, the data strongly indicate that p19 might influence multiple G2/M regulators to cause G2/M arrest.
MicroRNA is a class of noncoding RNAs with 21-25nt in length that functions posttranscriptionally to repress targeted gene expression by either inhibiting protein translation or promoting mRNA degradation. Although a large number of microRNAs have been isolated, only a few of them have the known functions. Moreover, there are only limited reports on the roles of microRNA in HFV infection. To this end, we used bioinformatic approach to screen the potential microRNA targeting site(s) in the RNA genome of human foamy virus (HFV). We found one has-miR-491-5p targeting site in the coding region of Bell gene. The targeted sequence was isolated from HFV and inserted into the 3'UTR of pEGFP-C1. The EGFP expressions were significantly repressed by either the chemically synthesized or the vector expressed has-miR-491-5p. Further, the repression could be rescued with either the chemically modified miRNA inhibitor or the overexpression of p19. Study indicated that has-miR-491-5p mediated posttranscriptionally gene repression occurred at mRNA rather than protein level. Finally, has-miR-491-5p could effectively blocked Bell expressions from both expression vector and HFV viral genome. Thus, the established system might be useful for the study of HFV replication and gene regulation.
In conclusion, some key regulatory proteins such as Borf1 and P19 produced from early viral infection have major influences on not only viral genome replication but also host cell cycle progression such as cell cycle arrest, which can be induced by the alterations of cell cycle related genes. In additoion, the host may exert its many defense mechanisms against viral invasion. One of the choices that the virus uses for self-defense might be to induce posttranscriptional gene silencing mediated by target site-specific microRNA. For example, the host miR-491 might inhibit HFV viral replication by miRNA-mediated posttranscriptional gene repression to down-regulate the expression of transcriptional activator Bell. This type of gene repression mediated by miR-491 may offer a good advantage for HFV to establish viral latency.
引文
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