Luperchio Adeline M, Jónsson Stefán R, Salamango Daniel J
Department of Microbiology and Immunology, Stony Brook University, Stony Brook, New York, NY 11794, USA.
Institute for Experimental Pathology, University of Iceland, Keldur, 112 Reykjavik, Iceland.
Viruses. 2022 Aug 1;14(8):1701. doi: 10.3390/v14081701.
The canonical function of lentiviral Vif proteins is to counteract the mutagenic potential of APOBEC3 antiviral restriction factors. However, recent studies have discovered that Vif proteins from diverse HIV-1 and simian immunodeficiency virus (SIV) isolates degrade cellular B56 phosphoregulators to remodel the host phosphoproteome and induce G2/M cell cycle arrest. Here, we evaluate the conservation of this activity among non-primate lentiviral Vif proteins using fluorescence-based degradation assays and demonstrate that maedi-visna virus (MVV) Vif efficiently degrades all five B56 family members. Testing an extensive panel of single amino acid substitution mutants revealed that MVV Vif recognizes B56 proteins through a conserved network of electrostatic interactions. Furthermore, experiments using genetic and pharmacologic approaches demonstrate that degradation of B56 proteins requires the cellular cofactor cyclophilin A. Lastly, MVV Vif-mediated depletion of B56 proteins induces a potent G2/M cell cycle arrest phenotype. Therefore, remodeling of the cellular phosphoproteome and induction of G2/M cell cycle arrest are ancient and conserved functions of lentiviral Vif proteins, which suggests that they are advantageous for lentiviral pathogenesis.
慢病毒Vif蛋白的典型功能是对抗APOBEC3抗病毒限制因子的诱变潜力。然而，最近的研究发现，来自不同HIV-1和猴免疫缺陷病毒（SIV）分离株的Vif蛋白会降解细胞B56磷酸调节因子，以重塑宿主磷酸化蛋白质组并诱导G2/M期细胞周期停滞。在这里，我们使用基于荧光的降解试验评估了非灵长类慢病毒Vif蛋白中这种活性的保守性，并证明梅迪-维斯纳病毒（MVV）Vif能有效降解所有五个B56家族成员。对大量单氨基酸取代突变体进行测试表明，MVV Vif通过一个保守的静电相互作用网络识别B56蛋白。此外，使用遗传和药理学方法进行的实验表明，B56蛋白的降解需要细胞辅因子亲环蛋白A。最后，MVV Vif介导的B56蛋白耗竭诱导了一种强大的G2/M期细胞周期停滞表型。因此，重塑细胞磷酸化蛋白质组和诱导G2/M期细胞周期停滞是慢病毒Vif蛋白古老且保守的功能，这表明它们对慢病毒发病机制具有优势。
