Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA.
Divisions of Human Biology and Basic Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Nature. 2023 Mar;615(7953):728-733. doi: 10.1038/s41586-023-05779-1. Epub 2023 Feb 8.
The APOBEC3 (A3) proteins are host antiviral cellular proteins that hypermutate the viral genome of diverse viral families. In retroviruses, this process requires A3 packaging into viral particles. The lentiviruses encode a protein, Vif, that antagonizes A3 family members by targeting them for degradation. Diversification of A3 allows host escape from Vif whereas adaptations in Vif enable cross-species transmission of primate lentiviruses. How this 'molecular arms race' plays out at the structural level is unknown. Here, we report the cryogenic electron microscopy structure of human APOBEC3G (A3G) bound to HIV-1 Vif, and the hijacked cellular proteins that promote ubiquitin-mediated proteolysis. A small surface explains the molecular arms race, including a cross-species transmission event that led to the birth of HIV-1. Unexpectedly, we find that RNA is a molecular glue for the Vif-A3G interaction, enabling Vif to repress A3G by ubiquitin-dependent and -independent mechanisms. Our results suggest a model in which Vif antagonizes A3G by intercepting it in its most dangerous form for the virus-when bound to RNA and on the pathway to packaging-to prevent viral restriction. By engaging essential surfaces required for restriction, Vif exploits a vulnerability in A3G, suggesting a general mechanism by which RNA binding helps to position key residues necessary for viral antagonism of a host antiviral gene.
APOBEC3（A3）蛋白是宿主抗病毒的细胞蛋白，可使多种病毒家族的病毒基因组发生超突变。在逆转录病毒中，这一过程需要 A3 包装到病毒颗粒中。慢病毒编码一种蛋白 Vif，通过靶向 A3 家族成员使其降解来拮抗 A3 家族成员。A3 的多样化使宿主能够逃避 Vif，而 Vif 的适应性使灵长类慢病毒能够在物种间传播。这种“分子军备竞赛”在结构水平上是如何发挥作用的尚不清楚。在这里，我们报告了与人免疫缺陷病毒 1（HIV-1）Vif 结合的人 APOBEC3G（A3G）的低温电子显微镜结构，以及促进泛素介导的蛋白水解的被劫持的细胞蛋白。一个小的表面解释了分子军备竞赛，包括一个导致 HIV-1 诞生的跨物种传播事件。出乎意料的是，我们发现 RNA 是 Vif-A3G 相互作用的分子胶，使 Vif 能够通过依赖和不依赖泛素的机制抑制 A3G。我们的结果提出了一个模型，即 Vif 通过在与 RNA 结合并在包装途径上时拦截对病毒最危险的 A3G 形式来拮抗 A3G，以防止病毒限制。通过结合限制所必需的基本表面，Vif 利用了 A3G 的一个弱点，这表明 RNA 结合有助于将病毒拮抗宿主抗病毒基因所必需的关键残基定位的一般机制。
