免疫调节因子ABIN1抑制HIV-1复制的机制研究

发布时间：2018-04-25 22:40

本文选题：HIV-1 + ABIN1　；参考：《武汉大学》2017年博士论文

【摘要】：获得性免疫缺陷综合征(艾滋病)是在全世界范围内广泛流行的一种疾病,造成这种疾病的病因学源头是人免疫缺陷病毒(HIV)的感染。HIV是一种逆转录病毒,它包括HIV-1和HIV-2,其中HIV-1是造成疾病的主要病毒亚型。作为逆转录病毒,HIV-1在进入细胞后首先整合到宿主细胞的染色体中,根据细胞内的环境,它可以启动复制周期,也可以变成潜伏感染状态,在合适的时机爆发,引起机体的病理损伤。HIV-1主要通过血液、体液、性和母婴垂直传播。在当前HIV-1感染是无法治愈的,是生命科学研究的热点。A20-BindingInhibitorofNF-κB activation(ABIN1)是一个重要的免疫调节因子,它与人体免疫系统的炎症反应关系密切。早先有报道,ABIN1参与了调控HIV-1的复制过程,但是其机制并不清楚。在本研究中,我们发现,ABIN1是一个HIV-1转录的抑制因子,因为ABIN1蛋白水平的下调无论是在Jurkat细胞系,还是人原代CD4+ T细胞中都能促进HIV-1的复制。在病毒的生活周期过程中,对ABIN1基因表达进行敲低可特异性地促进已经整合到宿主染色体的HIV-1基因组的转录,对此前的病毒侵染过程则没有影响。实验表明,ABIN1可以特异性地抑制原癌基因HDM2催化的Tat在K71位点发生的K63类型的泛素化,而这一位点的泛素化对于Tat的转录激活功能是非常重要的。而且,ABIN1中UBAN结构域的泛素链结合活性对此抑制作用是必需的。免疫荧光实验证明ABI1N可以通过将HDM2阻滞在细胞质内,抑制它对Tat的泛素化作用。我们最终得出结论,ABIN1是一个通过调节Tat泛素化从而抑制HIV-1 mRNA转录的内源性抑制蛋白。
[Abstract]:Acquired immunodeficiency syndrome (AIDS) is a disease that is widespread worldwide. The etiology of the disease is caused by human immunodeficiency virus (HIV) infection. HIV is a retrovirus. It includes HIV-1 and HIV-2, where HIV-1 is the main viral subtype causing disease. As a retrovirus, HIV-1 is first integrated into the chromosomes of the host cells when it enters the cell. Depending on the cell environment, it can initiate the replication cycle, or it can become a latent infection, erupting at the right time. Cause pathological damage. HIV-1 mainly through blood, body fluid, sex and mother-to-child vertical transmission. At present, HIV-1 infection is incurable and is a hot topic in life sciences. A20-BindingInhibitor of NF- 魏 B activation- ABIN1) is an important immunomodulatory factor, which is closely related to the inflammatory response of human immune system. It has been reported that ABIN1 is involved in the regulation of HIV-1 replication, but its mechanism is not clear. In this study, we found that ABIN1 is an inhibitor of HIV-1 transcription, because the down-regulation of ABIN1 protein level can promote the replication of HIV-1 in both Jurkat cell lines and human primary CD4 T cells. During the life cycle of the virus, knockout of ABIN1 gene expression can specifically promote the transcription of the HIV-1 genome which has been integrated into the host chromosome, but has no effect on the previous infection process of the virus. The results show that ABIN1 can specifically inhibit the K63 type ubiquitization of Tat catalyzed by proto-oncogene HDM2 at K71 site, which is very important for the transcriptional activation of Tat. Moreover, the ubiquitin chain binding activity of UBAN domain in ABIN1 is necessary. Immunofluorescence assay showed that ABI1N could block HDM2 into cytoplasm and inhibit its ubiquitin effect on Tat. We finally conclude that ABIN1 is an endogenous inhibitory protein that inhibits HIV-1 mRNA transcription by regulating Tat ubiquitization.
【学位授予单位】：武汉大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R373

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