Tian Chunjuan, Yu Xianghui, Zhang Wei, Wang Tao, Xu Rongzhen, Yu Xiao-Fang
Second Affiliated Hospital, Cancer Institute, School of Medicine, Zhejiang University, Hangzhou, China.
J Virol. 2006 Mar;80(6):3112-5. doi: 10.1128/JVI.80.6.3112-3115.2006.
APOBEC3G (A3G) and related cytidine deaminases, such as APOBEC3F (A3F), are potent inhibitors of retroviruses. Formation of infectious human immunodeficiency virus type 1 (HIV-1) requires suppression of multiple cytidine deaminases by Vif. Whether HIV-1 Vif recognizes various APOBEC3 proteins through a common mechanism is unclear. The domains in Vif that mediate APOBEC3 recognitions are also poorly defined. The N-terminal region of HIV-1 Vif is unusually rich in Trp residues, which are highly conserved. In the present study, we examined the role of these Trp residues in the suppression of APOBEC3 proteins by HIV-1 Vif. We found that most of the highly conserved Trp residues were required for efficient suppression of both A3G and A3F, but some of these residues were selectively required for the suppression of A3F but not A3G. Mutant Vif molecules in which Ala was substituted for Trp79 and, to a lesser extent, for Trp11 remained competent for A3G interaction and its suppression; however, they were defective for A3F interaction and therefore could not efficiently suppress the antiviral activity of A3F. Interestingly, while the HIV-1 Vif-mediated degradation of A3G was not affected by the different C-terminal tag peptides, that of A3F was significantly influenced by its C-terminal tags. These data indicate that the mechanisms by which HIV-1 Vif recognizes its target molecules, A3G and A3F, are not identical. The fact that several highly conserved residues in Vif are required for the suppression of A3F but not that of A3G suggests a critical role for A3F in the restriction of HIV-1 in vivo.
载脂蛋白B mRNA编辑酶催化多肽样蛋白3G（APOBEC3G，A3G）及相关胞苷脱氨酶，如载脂蛋白B mRNA编辑酶催化多肽样蛋白3F（APOBEC3F，A3F），是逆转录病毒的强效抑制剂。1型人类免疫缺陷病毒（HIV-1）形成具有感染性的病毒颗粒需要Vif蛋白抑制多种胞苷脱氨酶。目前尚不清楚HIV-1 Vif蛋白是否通过共同机制识别各种APOBEC3蛋白。介导APOBEC3识别的Vif蛋白结构域也尚未明确界定。HIV-1 Vif蛋白的N端区域色氨酸残基异常丰富，且高度保守。在本研究中，我们探究了这些色氨酸残基在HIV-1 Vif蛋白抑制APOBEC3蛋白过程中的作用。我们发现，大部分高度保守的色氨酸残基对于有效抑制A3G和A3F都是必需的，但其中一些残基仅对抑制A3F是必需的，对抑制A3G并非必需。用丙氨酸替代色氨酸79以及在较小程度上替代色氨酸11的突变Vif分子仍能与A3G相互作用并抑制A3G；然而，它们与A3F的相互作用存在缺陷，因此无法有效抑制A3F的抗病毒活性。有趣的是，虽然HIV-1 Vif蛋白介导的A3G降解不受不同C端标签肽的影响，但A3F的降解却受到其C端标签的显著影响。这些数据表明，HIV-1 Vif蛋白识别其靶分子A3G和A3F的机制并不相同。Vif蛋白中几个高度保守的残基对抑制A3F是必需的，但对抑制A3G并非必需，这一事实表明A3F在体内限制HIV-1方面起着关键作用。
