PLoS Pathogens | |
Evolutionary Toggling of Vpx/Vpr Specificity Results in Divergent Recognition of the Restriction Factor SAMHD1 | |
Chuanping Wang1  Jacek Skowronski1  Jinwoo Ahn2  Jennifer Mehrens2  Oliver I. Fregoso3  Michael Emerman3  | |
[1] Department of Molecular Biology and Microbiology, Case Western Reserve School of Medicine, Cleveland, Ohio, United States of America;Department of Structural Biology and Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America;Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America | |
关键词: Viral evolution; HIV-2; Primates; 293T cells; Evolutionary immunology; Amino acid analysis; Molecular evolution; Phylogenetic analysis; | |
DOI : 10.1371/journal.ppat.1003496 | |
学科分类:生物科学(综合) | |
来源: Public Library of Science | |
【 摘 要 】
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.
【 授权许可】
CC BY
【 预 览 】
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