HIV-1 Vpr激活细胞NF-κB信号通路分子机制的研究
摘要
Vpr是由人类免疫缺陷病毒Ⅰ型(HIV-1)编码的辅助蛋白。Vpr蛋白在病毒感染晚期表达,通过与Gagp6直接相互作用被包装到病毒颗粒中。Vpr在HIV-1复制及致病性等方面发挥重要作用,特别是能够在病毒感染早期改变细胞环境,使之有利于病毒复制。vpr基因的缺失会导致病毒复制能力显著下降。Vpr具有多种功能,包括可调节细胞NF-κB在内的多条信号通路,但Vpr对NF-κB信号通路的确切作用及其中的分子机制尚不明确。本文对Vpr与NF-κB信号通路的关系展开研究,获得相关实验数据如下：
1.证实Vpr可同时激活NF-kB经典和非经典信号通路：发现在HIV-1感染早期,病毒颗粒包装的Vpr能增强IκBα的磷酸化；同时,Vpr可以促进p65磷酸化及入核并最终激活NF-κB报告基因；过表达Vpr及病毒颗粒携带的Vpr均能引起p100的磷酸化,促进p100剪切为p52,从而活化非经典通路。
2.Vpr与NF-κB经典和非经典信号通路上游的IKKα和IKKβ存在相互作用,并调节二者的磷酸化；利用RNA干扰技术下调细胞内源p65、RelB、IKKα及IKKP的表达,发现Vpr对NF-κB信号通路的激活作用明显减弱。
3.通过免疫共沉淀实验对IKK复合物上游关键调节因子的筛选,发现Vpr与TRAF6及TAK1在体内存在相互作用,不与TRAF2及TAB1相互作用。但Vpr并不能影响TRAF6的自身泛素化。过表达和病毒感染两个层面均证实Vpr可在多种细胞中增强TAK1第187位苏氨酸(Thr187)的磷酸化,导致底物蛋白IKKα、IKKβ及MKK7的磷酸化,进而活化下游信号通路；同时,Vpr对TAK1的磷酸化依赖于TAB1及TRAF6;此外,Vpr通过募集TAB3促进TAK1的泛素化。
4.对Vpr活化NF-κB信号通路后对自身功能的影响进行初探：在NF-κB信号通路关键蛋白下调的细胞系中,检测Vpr对HIV-1LTR的激活作用,结果表明,Vpr介导的NF-κB活化促进了其对LTR的激活作用；进一步通过流式细胞术分析了Vpr在这些细胞系中诱导细胞周期G2/M期停滞的能力,初步证明NF-κB信号通路的激活有助于Vpr行使细胞周期停滞功能。
综上所述,本文证实了HIV-1感染宿主细胞早期,Vpr能够激活细胞内NF-κB经典和非经典信号通路,并初步阐明其中的分子机制：Vpr一方面通过增强IKKα及IKKβ的磷酸化,另一方面通过结合并增强TAK1的活性,共同实现了“劫持”NF-κB信号通路的目的,并促进自身LTR的转录、引起细胞周期停滞在G2/M期,从而有利于病毒的复制。
Viral protein R (Vpr) is an accessory protein of human immunodeficiency virus type I (HIV-1). Vpr is expressed at the late stage of HIV-1infection and incorporated into virus particles through a direct interaction with the p6domain of Gag. Vpr plays an important role in HIV-1replication and pathogenesis, especially by conferring a favorable cellular environment for efficient replication of HIV-1. Deletion of vpr reduces viral replication. Multiple functions have been discovered for Vpr, including the regulation of cellular NF-κB signaling pathway. But the exact role of Vpr on NF-κB signaling pathway remains unclear. And the detailed mechanisms still need to be illustrated. This study focused on the relationship between Vpr and NF-κB and the main results are listed below.
1. We confirmed that Vpr can activate canonical and non-canonical NF-κB signaling pathway. We found that at the early stage of HIV-1infection, Vpr, in the context of HIV-1virions, increased the phosphorylation of IκBα. In the meantime, Vpr elevated the phosphorylation and the nuclear transportation of p65, and stimulated the expression of NF-κB reporter gene in a dose-dependent manner. Furthermore, both ectopic expressed and virion-associated Vpr induced the phosphorylation of p100, and the processing of p100into p52, which resulted in the activation of non-canonical NF-κB pathway.
2. Immunoprecipitation assay gave the clues that Vpr interacted with IKKa and IKKP which are the upstream kinases of the canonical and non-canonical NF-κB pathway. And Vpr regulated the phosphorylation of IKKa and IKKβ.In addition, the activation of NF-κB reporter by Vpr is severely reduced in p65, RelB, IKKa or IKKβ knockdown cell lines.
3. With the benefit of immunoprecipitation between Vpr and the upstream signaling factors of IKK complex, we found that Vpr interacted with TRAF6and TAK1, but not TRAF2or TAB1. But Vpr didn't affect the auto-ubiquitination of TRAF6. Over-expressed and virion-associated Vpr enhanced the auto-phosphorylation-of TAK1on Thr187in various cell lines, which brought about the phosphorylation of IKKα, IKKβ, and MKK7, and the activation of downstream signal cascade. The phosphorylation of TAK1by Vpr relied on TAB1and TRAF6. Moreover, Vpr could increase the ubiquitination of TAK1by recruiting TAB3.
4. Finally, we envisioned that NF-κB activation might affect the reported functions of Vpr. The HIV-1LTR reporter assay in NF-κB knockdown cell lines indicated that Vpr-mediated NF-κB activation promoted HIV-1LTR transcription. Additionally, preliminary results of Flow cytometry shown that NF-κB activation promoted Vpr-induced cell cycle G2/M arrest.
Collectively, in this study, we demonstrate that Vpr activates both canonical and non-canonical NF-κB pathway at the early stage of HIV-1infection. The molecular mechanisms underlying this activation reveal that Vpr employs two patterns to hijack host NF-κB signaling pathway.(1) Vpr increases the phosphorylation of IKKa and IKKβ,(2) Vpr interacts with TAK1and elevated its activation. This results in the promotion of HIV-1LTR transcription, the cell cycle G2/M phase arrest and finally the virus replication.
1.证实Vpr可同时激活NF-kB经典和非经典信号通路：发现在HIV-1感染早期,病毒颗粒包装的Vpr能增强IκBα的磷酸化；同时,Vpr可以促进p65磷酸化及入核并最终激活NF-κB报告基因；过表达Vpr及病毒颗粒携带的Vpr均能引起p100的磷酸化,促进p100剪切为p52,从而活化非经典通路。
2.Vpr与NF-κB经典和非经典信号通路上游的IKKα和IKKβ存在相互作用,并调节二者的磷酸化；利用RNA干扰技术下调细胞内源p65、RelB、IKKα及IKKP的表达,发现Vpr对NF-κB信号通路的激活作用明显减弱。
3.通过免疫共沉淀实验对IKK复合物上游关键调节因子的筛选,发现Vpr与TRAF6及TAK1在体内存在相互作用,不与TRAF2及TAB1相互作用。但Vpr并不能影响TRAF6的自身泛素化。过表达和病毒感染两个层面均证实Vpr可在多种细胞中增强TAK1第187位苏氨酸(Thr187)的磷酸化,导致底物蛋白IKKα、IKKβ及MKK7的磷酸化,进而活化下游信号通路；同时,Vpr对TAK1的磷酸化依赖于TAB1及TRAF6;此外,Vpr通过募集TAB3促进TAK1的泛素化。
4.对Vpr活化NF-κB信号通路后对自身功能的影响进行初探：在NF-κB信号通路关键蛋白下调的细胞系中,检测Vpr对HIV-1LTR的激活作用,结果表明,Vpr介导的NF-κB活化促进了其对LTR的激活作用；进一步通过流式细胞术分析了Vpr在这些细胞系中诱导细胞周期G2/M期停滞的能力,初步证明NF-κB信号通路的激活有助于Vpr行使细胞周期停滞功能。
综上所述,本文证实了HIV-1感染宿主细胞早期,Vpr能够激活细胞内NF-κB经典和非经典信号通路,并初步阐明其中的分子机制：Vpr一方面通过增强IKKα及IKKβ的磷酸化,另一方面通过结合并增强TAK1的活性,共同实现了“劫持”NF-κB信号通路的目的,并促进自身LTR的转录、引起细胞周期停滞在G2/M期,从而有利于病毒的复制。
Viral protein R (Vpr) is an accessory protein of human immunodeficiency virus type I (HIV-1). Vpr is expressed at the late stage of HIV-1infection and incorporated into virus particles through a direct interaction with the p6domain of Gag. Vpr plays an important role in HIV-1replication and pathogenesis, especially by conferring a favorable cellular environment for efficient replication of HIV-1. Deletion of vpr reduces viral replication. Multiple functions have been discovered for Vpr, including the regulation of cellular NF-κB signaling pathway. But the exact role of Vpr on NF-κB signaling pathway remains unclear. And the detailed mechanisms still need to be illustrated. This study focused on the relationship between Vpr and NF-κB and the main results are listed below.
1. We confirmed that Vpr can activate canonical and non-canonical NF-κB signaling pathway. We found that at the early stage of HIV-1infection, Vpr, in the context of HIV-1virions, increased the phosphorylation of IκBα. In the meantime, Vpr elevated the phosphorylation and the nuclear transportation of p65, and stimulated the expression of NF-κB reporter gene in a dose-dependent manner. Furthermore, both ectopic expressed and virion-associated Vpr induced the phosphorylation of p100, and the processing of p100into p52, which resulted in the activation of non-canonical NF-κB pathway.
2. Immunoprecipitation assay gave the clues that Vpr interacted with IKKa and IKKP which are the upstream kinases of the canonical and non-canonical NF-κB pathway. And Vpr regulated the phosphorylation of IKKa and IKKβ.In addition, the activation of NF-κB reporter by Vpr is severely reduced in p65, RelB, IKKa or IKKβ knockdown cell lines.
3. With the benefit of immunoprecipitation between Vpr and the upstream signaling factors of IKK complex, we found that Vpr interacted with TRAF6and TAK1, but not TRAF2or TAB1. But Vpr didn't affect the auto-ubiquitination of TRAF6. Over-expressed and virion-associated Vpr enhanced the auto-phosphorylation-of TAK1on Thr187in various cell lines, which brought about the phosphorylation of IKKα, IKKβ, and MKK7, and the activation of downstream signal cascade. The phosphorylation of TAK1by Vpr relied on TAB1and TRAF6. Moreover, Vpr could increase the ubiquitination of TAK1by recruiting TAB3.
4. Finally, we envisioned that NF-κB activation might affect the reported functions of Vpr. The HIV-1LTR reporter assay in NF-κB knockdown cell lines indicated that Vpr-mediated NF-κB activation promoted HIV-1LTR transcription. Additionally, preliminary results of Flow cytometry shown that NF-κB activation promoted Vpr-induced cell cycle G2/M arrest.
Collectively, in this study, we demonstrate that Vpr activates both canonical and non-canonical NF-κB pathway at the early stage of HIV-1infection. The molecular mechanisms underlying this activation reveal that Vpr employs two patterns to hijack host NF-κB signaling pathway.(1) Vpr increases the phosphorylation of IKKa and IKKβ,(2) Vpr interacts with TAK1and elevated its activation. This results in the promotion of HIV-1LTR transcription, the cell cycle G2/M phase arrest and finally the virus replication.
引文
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