HIV-1 viral infectivity factor interacts with TP53 to induce G2 cell cycle arrest and positively regulate viral replication
HIV-1 viral infectivity factor interacts with TP53 to induce G2 cell cycle arrest and positively regulate viral replication
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DOI：
10.1073/pnas.1008076107
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发表时间：
2010-11-30
影响因子：
11.1
通讯作者：
Takaori-Kondo, Akifumi
中科院分区：
文献类型：
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作者：
Izumi, Taisuke;Io, Katsuhiro;Takaori-Kondo, Akifumi
病毒感染因子是HIV-1基因组编码的一种辅助蛋白，可诱导G2细胞周期阻滞；然而，其生物学意义和机制尚不清楚。在这里，我们证明了TP53途径参与了vif介导的G2细胞周期阻滞。Vif通过阻断mdm2介导的泛素化和TP53的核输出来增强TP53的稳定性和转录活性。此外，Vif以依赖tp53的方式引起G2细胞周期阻滞。HXB2 Vif缺乏对TP53的这些活性，不能诱导G2细胞周期阻滞。利用诱变技术，我们证明了该功能的关键残基位于Vif的n端区域。最后，我们构建了具有NL4-3/HXB2嵌合Vif缺陷的NL4-3突变病毒，该突变病毒在表达TP53的T细胞中复制的效率低于野生型NL4-3病毒。这些数据表明，Vif通过与TP53/MDM2轴的功能相互作用诱导G2细胞周期阻滞，并且Vif诱导的G2细胞周期阻滞对HIV-1复制具有积极作用。本报告论证了vif介导的G2细胞周期阻滞对HIV-1感染的分子机制和生物学意义。
Viral infectivity factor, an accessory protein encoded in the HIV-1 genome, induces G2 cell cycle arrest; however, the biological significance and mechanism(s) remain totally unclear. Here we demonstrate that the TP53 pathway is involved in Vif-mediated G2 cell cycle arrest. Vif enhances the stability and transcriptional activity of TP53 by blocking the MDM2-mediated ubiquitination and nuclear export of TP53. Furthermore, Vif causes G2 cell cycle arrest in a TP53-dependent manner. HXB2 Vif lacks these activities toward TP53 and cannot induce G2 cell cycle arrest. Using mutagenesis, we demonstrate that the critical residues for this function are located in the N-terminal region of Vif. Finally, we construct a mutant NL4-3 virus with an NL4-3/HXB2 chimeric Vif defective for the ability to induce cell cycle arrest and show that the mutant virus replicates less effectively than the wild-type NL4-3 virus in T cells expressing TP53. These data imply that Vif induces G2 cell cycle arrest through functional interaction with the TP53/MDM2 axis and that the G2 cell cycle arrest induced by Vif has a positive effect on HIV-1 replication. This report demonstrates the molecular mechanisms and the biological significance of Vif-mediated G2 cell cycle arrest for HIV-1 infection.