HPV16主要衣壳蛋白L1与hnRNP H1的相互作用及其功能
摘要
流行病学和相关研究证实人乳头瘤病毒(HPV)感染与尖锐湿疣、宮颈上皮瘤样增生和宫颈癌的发生关系密切。HPV感染机体后各种病毒基因的表达是受严格调控的,尤其是晚期基因,在未分化的细胞中几乎不表达,随着细胞分裂,病毒基因组随子细胞上移到表皮上层后,晚期蛋白的表达才被启动。这种分化依赖的晚期蛋白表达调控机制尚不明确。
在以往的研究中发现,晚期蛋白在转录后水平受多种负调节元件的控制,其中早期多聚腺苷酸化信号(pAE)在晚期基因的转录后调控中起到核心的作用,它能使mRNA的转录提前终止,在HPV16 L2的N端有一个GU含量丰富的序列(GU-rich sequence,GRS),是hnRNP H1蛋白结合位点,能够增强pAE的活性,进一步抑制晚期蛋白的表达。hnRNPH1在细胞中的分布水平有随着细胞的分化而降低的特点,晚期蛋白表达的组织特异性很可能与hnRNP H1的表达有关。
我们用免疫共沉淀技术发现hnRNP H1与HPV16 L1蛋白有相互作用,并证实这种相互作用是天然状态下存在的。我们构建了一个模拟HPV转录调控的质粒模型(pGPG),用两个GFP分别代替早期基因和晚期基因,中间加以pAE和下游的GRS序列。通过检测下游的GFP(G2)的RNA以及蛋白质的表达,来反映hnRNP H1蛋白及L1对晚期蛋白转录翻译的影响。在293F了细胞中转染pGPG质粒,几乎检测不到G2的转录产物,蛋白表达量也很低,沉默hnRNP H1基因后,G2的转录和表达量大大提高,印证了hnRNP H1对晚期蛋白的转录抑制效应起重要作用。我们首次发现:HPV16 L1的表达能够有效地提高G2的转录和蛋白表达水平,在HeLa和Huh7等细胞上也发现相同的现象,将hnRNP H1沉默后再转染HPV16 L1质粒,发现在没有H1的情况下,L1对G2的表达没有额外的刺激效应。提示HPV16 L1对晚期蛋白表达的提高可能是通过L1与hnRNPH1结合,抑制了hnRNP H1的功能来实现的。在病毒的感染过程中,L1蛋白很可能参与了晚期基因的转录后调控,对自身的表达有正协同的效应。L1与hnRNPH1相互阻遏,hnRNP H1表达过高时L1的表达被抑制,在分化的细胞中hnRNPH1的表达量降低,pAE活性不高,晚期基因可以通读、表达,随着L1蛋白表达量增多并结合到hnRNP H1上,hnRNP H1失活,最终L1蛋白得以大量表达,启动病毒成熟的后续过程。本文章为更进一步揭示HPV晚期蛋白的表达和病毒生活周期的调控规律提供了一些思路,为HPV引发的多种疾病的致病机理提供理论支持,并为相关治疗药物的研发提供有利的启示。
It has been confirmed that the infection of HPV is associated with genital warts and various forms of cancer in men and women.Expression of viral gene,especially the late gene,is tightly controlled while these late gene will not expressed in less differentiated cells.Along with cell division,viral genome move upward to the most superficial epithelium layer,and that initiate the late gene expression.However the mechanism of differentiation dependent late gene expression is not totally clear.
The expression of the late genes is negatively regulated by various factors at the post-transcriptional level.The most key point is the early polyadenylated signal(pAE), which can prevent virus from reading-through into the late region.A GU-rich sequence (GRS) was found downstream of the pAE in HPV16 L2 gene which is also a binding site of hnRNP H1.The binding can enhance the efficiency of pAE and down-regulate the expression of the late gene.It was noticed that in cervical epithelia the expression of hnRNP H1 is gradually declined with the differentiation of the cells.It may be an explanation of why the late gene expression acts in a differentiation-dependent manner.
We found an natively existed interaction between HPV16 L1 and hnRNP H1 with co-immunoprecipitation.A plasmid pGPG has been constructed to simulate the transcriptional regulation of papillomavirus.We used two GFP genes to stand for the early and late gene,and inserted the pAE and GRS between them.Assessment of the expression of downstream GFP(G2) could figure out the effects of hnRNP H1 and HPV16 L1 in the late gene expression.293FT cells were transfected with pGPG,and hardly any G2 mRNA and protein could be detected.After silencing the hnRNP H1 gene in 293FT the G2 expression level became high and that supported the view hnRNP H1 plays an important role in down-regulating the late gene expression.We primarily found that HPV16 L1 protein could largely activate the G2 expression.Similar results were also observed in HeLa and Huh7 cells.While L1 in the hnRNP H1 absent cells couldn't bring about extra effects on G2 expression compared with L1 negative cells.It is suspected that HPV16 L1 could increase the late gene expression in our model.The mechanism might lie in the interaction between hnRNP H1 and L1 which inhibit the function of H1 protein. L1 might participate in the regulation of late gene expression in the course of HPV infection,and have a positive synergistic effect on the expression of itself.On the other hand,L1 and hnRNP H1 repress each other.When the expression of hnRNP H1 increases, the late gene expression will be inhibited.Whereas in the terminally differentiated cells, the level of hnRNP H1 was too much lower for pAE to function well.This caused the reading-through of the late region,followed by production of the late mRNAs encoding L1 and L2.More and more L1 protein bind to hnRNP H1 and break the balance between them which make even more late gene products and initiate some other processes impelling the maturation of virus.We hope our research could provide a clue for further understanding of the mechanism about HPV late protein expression and virus life cycle, and provide more experimental supports for interpreting the pathogenesis of HPV induced diseases,which might contribute to successful drug design of these diseases.
在以往的研究中发现,晚期蛋白在转录后水平受多种负调节元件的控制,其中早期多聚腺苷酸化信号(pAE)在晚期基因的转录后调控中起到核心的作用,它能使mRNA的转录提前终止,在HPV16 L2的N端有一个GU含量丰富的序列(GU-rich sequence,GRS),是hnRNP H1蛋白结合位点,能够增强pAE的活性,进一步抑制晚期蛋白的表达。hnRNPH1在细胞中的分布水平有随着细胞的分化而降低的特点,晚期蛋白表达的组织特异性很可能与hnRNP H1的表达有关。
我们用免疫共沉淀技术发现hnRNP H1与HPV16 L1蛋白有相互作用,并证实这种相互作用是天然状态下存在的。我们构建了一个模拟HPV转录调控的质粒模型(pGPG),用两个GFP分别代替早期基因和晚期基因,中间加以pAE和下游的GRS序列。通过检测下游的GFP(G2)的RNA以及蛋白质的表达,来反映hnRNP H1蛋白及L1对晚期蛋白转录翻译的影响。在293F了细胞中转染pGPG质粒,几乎检测不到G2的转录产物,蛋白表达量也很低,沉默hnRNP H1基因后,G2的转录和表达量大大提高,印证了hnRNP H1对晚期蛋白的转录抑制效应起重要作用。我们首次发现:HPV16 L1的表达能够有效地提高G2的转录和蛋白表达水平,在HeLa和Huh7等细胞上也发现相同的现象,将hnRNP H1沉默后再转染HPV16 L1质粒,发现在没有H1的情况下,L1对G2的表达没有额外的刺激效应。提示HPV16 L1对晚期蛋白表达的提高可能是通过L1与hnRNPH1结合,抑制了hnRNP H1的功能来实现的。在病毒的感染过程中,L1蛋白很可能参与了晚期基因的转录后调控,对自身的表达有正协同的效应。L1与hnRNPH1相互阻遏,hnRNP H1表达过高时L1的表达被抑制,在分化的细胞中hnRNPH1的表达量降低,pAE活性不高,晚期基因可以通读、表达,随着L1蛋白表达量增多并结合到hnRNP H1上,hnRNP H1失活,最终L1蛋白得以大量表达,启动病毒成熟的后续过程。本文章为更进一步揭示HPV晚期蛋白的表达和病毒生活周期的调控规律提供了一些思路,为HPV引发的多种疾病的致病机理提供理论支持,并为相关治疗药物的研发提供有利的启示。
It has been confirmed that the infection of HPV is associated with genital warts and various forms of cancer in men and women.Expression of viral gene,especially the late gene,is tightly controlled while these late gene will not expressed in less differentiated cells.Along with cell division,viral genome move upward to the most superficial epithelium layer,and that initiate the late gene expression.However the mechanism of differentiation dependent late gene expression is not totally clear.
The expression of the late genes is negatively regulated by various factors at the post-transcriptional level.The most key point is the early polyadenylated signal(pAE), which can prevent virus from reading-through into the late region.A GU-rich sequence (GRS) was found downstream of the pAE in HPV16 L2 gene which is also a binding site of hnRNP H1.The binding can enhance the efficiency of pAE and down-regulate the expression of the late gene.It was noticed that in cervical epithelia the expression of hnRNP H1 is gradually declined with the differentiation of the cells.It may be an explanation of why the late gene expression acts in a differentiation-dependent manner.
We found an natively existed interaction between HPV16 L1 and hnRNP H1 with co-immunoprecipitation.A plasmid pGPG has been constructed to simulate the transcriptional regulation of papillomavirus.We used two GFP genes to stand for the early and late gene,and inserted the pAE and GRS between them.Assessment of the expression of downstream GFP(G2) could figure out the effects of hnRNP H1 and HPV16 L1 in the late gene expression.293FT cells were transfected with pGPG,and hardly any G2 mRNA and protein could be detected.After silencing the hnRNP H1 gene in 293FT the G2 expression level became high and that supported the view hnRNP H1 plays an important role in down-regulating the late gene expression.We primarily found that HPV16 L1 protein could largely activate the G2 expression.Similar results were also observed in HeLa and Huh7 cells.While L1 in the hnRNP H1 absent cells couldn't bring about extra effects on G2 expression compared with L1 negative cells.It is suspected that HPV16 L1 could increase the late gene expression in our model.The mechanism might lie in the interaction between hnRNP H1 and L1 which inhibit the function of H1 protein. L1 might participate in the regulation of late gene expression in the course of HPV infection,and have a positive synergistic effect on the expression of itself.On the other hand,L1 and hnRNP H1 repress each other.When the expression of hnRNP H1 increases, the late gene expression will be inhibited.Whereas in the terminally differentiated cells, the level of hnRNP H1 was too much lower for pAE to function well.This caused the reading-through of the late region,followed by production of the late mRNAs encoding L1 and L2.More and more L1 protein bind to hnRNP H1 and break the balance between them which make even more late gene products and initiate some other processes impelling the maturation of virus.We hope our research could provide a clue for further understanding of the mechanism about HPV late protein expression and virus life cycle, and provide more experimental supports for interpreting the pathogenesis of HPV induced diseases,which might contribute to successful drug design of these diseases.
引文
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