FAT10在H5N1病毒及甲型H1N1流感病毒复制及诱导人呼吸道上皮细胞凋亡中的作用
摘要
由于缺乏有效的预防和治疗手段,H5N1病毒仍是威胁全球健康的一个严重的长期隐患。在人感染HSN1病毒的多数病例中,HSN1病毒能引起严重的临床症状,导致病情快速恶化和病人极高的病死率。许多研究都试图揭示其毒力增强的遗传基础和致病机理,较强的病毒复制能力和病毒感染引起的细胞因子风暴被认为在其致病机理中占重要位置。利用高通量组学研究手段,解析H5N1病毒和宿主细胞之间的相互作用,找到在H5N1病毒生活周期中起重要作用的宿主因子,将有助于开发更为广谱且不易产生耐药性的治疗药物。
本文研究的主要对象类泛素蛋白FAT10(又称泛素D, Ubiquitin D, UBD)即是从H5N1病毒感染小鼠肺组织的基因表达谱分析中筛选出来的一个重要宿主因子。我们发现H5N1病毒的感染在小鼠肺组织和多种人呼吸道上皮细胞中均能够引起FAT10表达水平显著升高。进一步的研究表明,FAT10在H5N1病毒复制过程中起重要作用。敲减FAT10蛋白能够抑制H5N1病毒M1基因和NP蛋白的表达。通过对FAT10ylation系统重要组分UBA6和USE1的敲减实验表明,FAT10ylation系统在H5N1病毒复制中也发挥重要作用。
通过对H5N1病毒蛋白及dsRNA类似物poly (IC)的筛选,我们发现poly (IC)能够通过RIG-1-p65通路诱导FAT10表达显著上调。在对FAT10下游作用蛋白的研究中发现,H5N1病毒感染时p62能够作为FAT10底物与其结合。敲减p62后H5N1病毒M1和NP表达水平显著升高,说明p62对H5N1病毒的复制起限制性作用。HSN1病毒感染后能引起STAT1磷酸化水平升高,而敲减p62能使这一过程中的STAT1磷酸化水平降低,提示p62参与并调控H5N1病毒引起的JAK-STATl信号通路。
总之,本文揭示了FAT10在H5N1病毒复制过程的重要作用。这一发现不仅拓宽了我们对这一类泛素蛋白分子生物学功能的理解,更重要的是为针对H5N1病毒的治疗药物研发提供了新的思路和潜在的靶点。
H5N1病毒引起的免疫细胞和呼吸道上皮细胞死亡,是其重要的致病机制之一。在这一部分论文中主要对FAT10在H5N1病毒引起的细胞死亡中的作用展开了初步的探索。通过MTS实验检测细胞活力,我们发现敲减FAT10能显著改善A549、BEAS-2B、CNE-2Z细胞中H5N1病毒感染引起的细胞死亡。进一步的研究显示敲减FAT10能抑制H5N1病毒引起的caspase-3剪切活化,减少H5N1病毒引起凋亡的细胞比例,还能够抑制促凋亡因子TNFa和FASLG的mRNA表达水平。此外,通过检测LC3B的蛋白水平我们发现,敲减FAT10不能抑制H5N1病毒诱导的细胞自噬。
因此,我们的结论是FAT10在H5N1病毒引起的呼吸道上皮细胞死亡中起重要作用。敲减FAT10能够抑制H5N1病毒诱导的细胞凋亡,但不能抑制病毒诱导的细胞自噬。
2009甲型H1N1流感病毒具有强大的传播能力和较强的致病能力,包含来自猪H1N1流感病毒、人H3N2流感病毒和禽流感病毒的不同片段,其感染及死亡病例主要集中在青壮年,能够导致急性呼吸窘迫综合征(ARDS)等严重疾病。通过将我们实验室筛选到的一株甲流毒株A/Wenshan H1N1病毒感染人鼻咽癌细胞(CNE-2Z)作为模型,我们对FAT10在A/Wenshan H1N1病毒引起的细胞凋亡和病毒复制这两方面进行了初步研究。研究发现,敲减FAT10能够抑制A/Wenshan H1N1病毒感染引起的CNE-2Z细胞凋亡。在CNE-2Z细胞中敲减FAT10能够抑制病毒引起的caspase-3剪切活化,减少病毒感染后发生凋亡的细胞比例,还能够抑制促凋亡因子TNFa的表达水平。在CNE-2Z细胞中敲减FAT10能够抑制A/Wenshan H1N1病毒M1基因的mRNA水平。结合前两部分的研究,提示我们FAT10可能是流感病毒的一个普遍的宿主因子。
The avian influenza H5N1virus causes severe disease and high mortality, which makes it a major worldwide public health concern. The virus is capable of using the host cellular machinery for aspects of its life cycle. In this report, we discovered that FAT10, a ubiquitin-like protein, was induced by the live H5N1virus infection in mice and in the human respiratory epithelial cell lines A549, BEAS-2B and CNE-2Z. Further studies demonstrated that FAT10was crucial for the replication of the H5N1virus and that FAT10ylation was involved. The knockdown of FAT10expression significantly reduced H5N1viral replication, while the overexpression of FAT10proteins markedly increased viral replication. Poly(IC), the analogue of viral RNA, could significantly increase FAT10expression through the RIG-1-p65pathway, suggesting that FAT10elevation might be crucial for viral evasion of the immune system. The p62protein, which was confirmed to be a substrate of FAT10, might be involved in this process. The knockdown of p62expression in A549cells significantly reduced the phosphorylation of STAT1during live H5N1virus infection, which suggests that p62might be involved in the innate immunity response against H5N1virus infection. Taken together, our data suggest that FAT10elevation and FAT10ylation might be crucial in viral evasion of the immune system.
One of the pathogenesis of avian influenza H5N1virus is the virus-induced cell death of immune cells and respiratory tract epithelial cells. In this part of the thesis, we carried out preliminary exploration about the role of host factor FAT10in the cell death caused by H5N1virus. By measuring the cell viability through MTS, we found that the knockdown of FAT10could significantly improve the virus-induced death of respiratory tract epithelial cell, such as A549cell, BEAS-2B and CNE-2Z cell. Further study indicated that knockdown of FAT10could repress the virus-induced proteolytic cleavage of caspase-3, reduce the proportion of apoptotic cells and inhibit the mRNA level of pro-apoptotic factor TNFa and FASLG. Besides, by monitoring the protein level of LC3B, which is one of the main markers of autophagy, we found that the knockdown of FAT10could not inhibit the autophagy caused by H5N1virus infection.
In conclusion, we found that the host factor FAT10plays an important role in the virus-induced respiritory tract epithelial cell death. The cellular apoptotic process but not the cellular autophagy process could be inhibited by the knockdown of FAT10.
2009pandemic H1N1virus possesses high transmissibilit and pathogenic potentiality, and its genome includes different segments from classic swine H1N1, Human H3N2and avian influenza. It could cause the acute respiratory distress syndrome (ARDS) and other severe diseases. A/Wenshan H1N1virus was studied as a strain of2009pandemic H1N1virus in our lab, causing severe apoptosis in CNE-2Z cells. Then we explored the role of FAT10in the apoptosis of CNE-2Z cells induced by A/Wenshan H1N1virus and also in the viral replication. In our research, we found that the knockdown of FAT10could inhibit the activation of caspase-3, reduce the apoptotic cell proportion, and repress the mRNA level of pro-apoptotic factor TNFa. The knockdown of FAT10could also repress the mRNA level of viral M1. Considering the first two parts of this thesis, we proposed that FAT10could be a general host factor during influenza virus infection.
本文研究的主要对象类泛素蛋白FAT10(又称泛素D, Ubiquitin D, UBD)即是从H5N1病毒感染小鼠肺组织的基因表达谱分析中筛选出来的一个重要宿主因子。我们发现H5N1病毒的感染在小鼠肺组织和多种人呼吸道上皮细胞中均能够引起FAT10表达水平显著升高。进一步的研究表明,FAT10在H5N1病毒复制过程中起重要作用。敲减FAT10蛋白能够抑制H5N1病毒M1基因和NP蛋白的表达。通过对FAT10ylation系统重要组分UBA6和USE1的敲减实验表明,FAT10ylation系统在H5N1病毒复制中也发挥重要作用。
通过对H5N1病毒蛋白及dsRNA类似物poly (IC)的筛选,我们发现poly (IC)能够通过RIG-1-p65通路诱导FAT10表达显著上调。在对FAT10下游作用蛋白的研究中发现,H5N1病毒感染时p62能够作为FAT10底物与其结合。敲减p62后H5N1病毒M1和NP表达水平显著升高,说明p62对H5N1病毒的复制起限制性作用。HSN1病毒感染后能引起STAT1磷酸化水平升高,而敲减p62能使这一过程中的STAT1磷酸化水平降低,提示p62参与并调控H5N1病毒引起的JAK-STATl信号通路。
总之,本文揭示了FAT10在H5N1病毒复制过程的重要作用。这一发现不仅拓宽了我们对这一类泛素蛋白分子生物学功能的理解,更重要的是为针对H5N1病毒的治疗药物研发提供了新的思路和潜在的靶点。
H5N1病毒引起的免疫细胞和呼吸道上皮细胞死亡,是其重要的致病机制之一。在这一部分论文中主要对FAT10在H5N1病毒引起的细胞死亡中的作用展开了初步的探索。通过MTS实验检测细胞活力,我们发现敲减FAT10能显著改善A549、BEAS-2B、CNE-2Z细胞中H5N1病毒感染引起的细胞死亡。进一步的研究显示敲减FAT10能抑制H5N1病毒引起的caspase-3剪切活化,减少H5N1病毒引起凋亡的细胞比例,还能够抑制促凋亡因子TNFa和FASLG的mRNA表达水平。此外,通过检测LC3B的蛋白水平我们发现,敲减FAT10不能抑制H5N1病毒诱导的细胞自噬。
因此,我们的结论是FAT10在H5N1病毒引起的呼吸道上皮细胞死亡中起重要作用。敲减FAT10能够抑制H5N1病毒诱导的细胞凋亡,但不能抑制病毒诱导的细胞自噬。
2009甲型H1N1流感病毒具有强大的传播能力和较强的致病能力,包含来自猪H1N1流感病毒、人H3N2流感病毒和禽流感病毒的不同片段,其感染及死亡病例主要集中在青壮年,能够导致急性呼吸窘迫综合征(ARDS)等严重疾病。通过将我们实验室筛选到的一株甲流毒株A/Wenshan H1N1病毒感染人鼻咽癌细胞(CNE-2Z)作为模型,我们对FAT10在A/Wenshan H1N1病毒引起的细胞凋亡和病毒复制这两方面进行了初步研究。研究发现,敲减FAT10能够抑制A/Wenshan H1N1病毒感染引起的CNE-2Z细胞凋亡。在CNE-2Z细胞中敲减FAT10能够抑制病毒引起的caspase-3剪切活化,减少病毒感染后发生凋亡的细胞比例,还能够抑制促凋亡因子TNFa的表达水平。在CNE-2Z细胞中敲减FAT10能够抑制A/Wenshan H1N1病毒M1基因的mRNA水平。结合前两部分的研究,提示我们FAT10可能是流感病毒的一个普遍的宿主因子。
The avian influenza H5N1virus causes severe disease and high mortality, which makes it a major worldwide public health concern. The virus is capable of using the host cellular machinery for aspects of its life cycle. In this report, we discovered that FAT10, a ubiquitin-like protein, was induced by the live H5N1virus infection in mice and in the human respiratory epithelial cell lines A549, BEAS-2B and CNE-2Z. Further studies demonstrated that FAT10was crucial for the replication of the H5N1virus and that FAT10ylation was involved. The knockdown of FAT10expression significantly reduced H5N1viral replication, while the overexpression of FAT10proteins markedly increased viral replication. Poly(IC), the analogue of viral RNA, could significantly increase FAT10expression through the RIG-1-p65pathway, suggesting that FAT10elevation might be crucial for viral evasion of the immune system. The p62protein, which was confirmed to be a substrate of FAT10, might be involved in this process. The knockdown of p62expression in A549cells significantly reduced the phosphorylation of STAT1during live H5N1virus infection, which suggests that p62might be involved in the innate immunity response against H5N1virus infection. Taken together, our data suggest that FAT10elevation and FAT10ylation might be crucial in viral evasion of the immune system.
One of the pathogenesis of avian influenza H5N1virus is the virus-induced cell death of immune cells and respiratory tract epithelial cells. In this part of the thesis, we carried out preliminary exploration about the role of host factor FAT10in the cell death caused by H5N1virus. By measuring the cell viability through MTS, we found that the knockdown of FAT10could significantly improve the virus-induced death of respiratory tract epithelial cell, such as A549cell, BEAS-2B and CNE-2Z cell. Further study indicated that knockdown of FAT10could repress the virus-induced proteolytic cleavage of caspase-3, reduce the proportion of apoptotic cells and inhibit the mRNA level of pro-apoptotic factor TNFa and FASLG. Besides, by monitoring the protein level of LC3B, which is one of the main markers of autophagy, we found that the knockdown of FAT10could not inhibit the autophagy caused by H5N1virus infection.
In conclusion, we found that the host factor FAT10plays an important role in the virus-induced respiritory tract epithelial cell death. The cellular apoptotic process but not the cellular autophagy process could be inhibited by the knockdown of FAT10.
2009pandemic H1N1virus possesses high transmissibilit and pathogenic potentiality, and its genome includes different segments from classic swine H1N1, Human H3N2and avian influenza. It could cause the acute respiratory distress syndrome (ARDS) and other severe diseases. A/Wenshan H1N1virus was studied as a strain of2009pandemic H1N1virus in our lab, causing severe apoptosis in CNE-2Z cells. Then we explored the role of FAT10in the apoptosis of CNE-2Z cells induced by A/Wenshan H1N1virus and also in the viral replication. In our research, we found that the knockdown of FAT10could inhibit the activation of caspase-3, reduce the apoptotic cell proportion, and repress the mRNA level of pro-apoptotic factor TNFa. The knockdown of FAT10could also repress the mRNA level of viral M1. Considering the first two parts of this thesis, we proposed that FAT10could be a general host factor during influenza virus infection.
引文
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