Evolutionary toggling of Vpx/Vpr specificity results in divergent recognition of the restriction factor SAMHD1.
Evolutionary toggling of Vpx/Vpr specificity results in divergent recognition of the restriction factor SAMHD1.
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DOI：
10.1371/journal.ppat.1003496
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Emerman M
中科院分区：
文献类型：
--
作者：
Fregoso OI;Ahn J;Wang C;Mehrens J;Skowronski J;Emerman M
SAMHD 1是一种宿主限制因子，可阻断HIV-1等慢病毒在骨髓细胞和静息T细胞中进行逆转录的能力。这种限制通过慢病毒辅助蛋白Vpx和Vpr（Vpx/Vpr）的表达而减轻，其靶向SAMHD 1用于蛋白酶体介导的降解。然而，SAMHD 1内Vpx/Vpr识别的确切决定因素仍不清楚。在这里，我们表明，在灵长类慢病毒Vpx/Vpr的进化引起了SAMHD 1和Vpx/Vpr之间的接口改变灵长类慢病毒进化过程中。使用多种HIV-2和SIV Vpx蛋白，我们表明，Vpx从HIV-2和SIVmac谱系，但不是Vpx从SIVmnd 2和SIVrcm谱系，需要的C-末端SAMHD 1的相互作用，泛素化和降解。另一方面，SAMHD 1的N-末端控制与来自SIVmnd 2和SIVrcm的Vpx的相互作用，但对来自HIV-2和SIVmac的Vpx几乎没有影响。此外，我们在这里表明，SAMHD 1识别的这种差异是进化动态的，与SAMHD 1的N-和C-末端的相互作用的重要性Vpx和Vpr切换慢病毒进化过程中。我们提出了一个模型来解释如何头到尾的SAMHD 1蛋白的构象有利于切换的相互作用位点的Vpx/Vpr在这个病毒宿主的军备竞赛。慢病毒蛋白质内的这种剧烈的功能差异突出了在慢病毒适应其宿主期间限制因子的病毒拮抗剂的进化动力学中的新可塑性。至少有40种野生灵长类动物感染了它们自己的慢病毒。这些感染中有许多是由跨物种传播引起的，随后是对新宿主的适应。宿主的抗病毒蛋白质，称为限制因子，其作用是防御已知的和新的病毒，因此与病毒蛋白质进行持续的军备竞赛。SAMHD 1是一种限制性因子，可阻断某些免疫细胞的慢病毒感染。然而，SAMHD 1被慢病毒蛋白Vpx和Vpr抵消。在这里，我们表明，Vpx和Vpr已经发展到识别SAMHD 1的不同接口，与SAMHD 1正在迅速发展以逃避这种识别的想法一致。此外，我们表明，虽然这种拮抗作用的网站一直在改变来回整个慢病毒的进化，Vpx和Vpr拮抗SAMHD 1的机制保持不变。这些数据说明了一种新的现象，其中存在限制因子及其病毒拮抗剂之间的不同识别的进化切换。
SAMHD1 is a host restriction factor that blocks the ability of lentiviruses such as HIV-1 to undergo reverse transcription in myeloid cells and resting T-cells. This restriction is alleviated by expression of the lentiviral accessory proteins Vpx and Vpr (Vpx/Vpr), which target SAMHD1 for proteasome-mediated degradation. However, the precise determinants within SAMHD1 for recognition by Vpx/Vpr remain unclear. Here we show that evolution of Vpx/Vpr in primate lentiviruses has caused the interface between SAMHD1 and Vpx/Vpr to alter during primate lentiviral evolution. Using multiple HIV-2 and SIV Vpx proteins, we show that Vpx from the HIV-2 and SIVmac lineage, but not Vpx from the SIVmnd2 and SIVrcm lineage, require the C-terminus of SAMHD1 for interaction, ubiquitylation, and degradation. On the other hand, the N-terminus of SAMHD1 governs interactions with Vpx from SIVmnd2 and SIVrcm, but has little effect on Vpx from HIV-2 and SIVmac. Furthermore, we show here that this difference in SAMHD1 recognition is evolutionarily dynamic, with the importance of the N- and C-terminus for interaction of SAMHD1 with Vpx and Vpr toggling during lentiviral evolution. We present a model to explain how the head-to-tail conformation of SAMHD1 proteins favors toggling of the interaction sites by Vpx/Vpr during this virus-host arms race. Such drastic functional divergence within a lentiviral protein highlights a novel plasticity in the evolutionary dynamics of viral antagonists for restriction factors during lentiviral adaptation to its hosts. At least 40 primate species in the wild are infected with their own lentivirus. Many of these infections arose from cross-species transmission followed by adaptation to a new host. Host antiviral proteins, called restriction factors, work to defend against both known and novel viruses and are thus engaged in a constant arms race with viral proteins. SAMHD1 is a restriction factor that blocks lentiviral infection of certain immune cells. However, SAMHD1 is counteracted by the lentiviral proteins Vpx and Vpr. Here we show that both Vpx and Vpr have evolved to recognize distinct interfaces of SAMHD1, consistent with the idea that SAMHD1 is rapidly evolving to evade this recognition. Furthermore, we show that while the site of this antagonism has been changing back and forth throughout lentiviral evolution, the mechanism by which Vpx and Vpr antagonize SAMHD1 has remained constant. These data illustrate a novel phenomenon in which there is an evolutionary toggling of divergent recognition between a restriction factor and its viral antagonist.
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