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Evolutionary Toggling of Vpx/Vpr Specificity Results in Divergent Recognition of the Restriction Factor SAMHD1

Fregoso, OI and Ahn, J and Wang, C and Mehrens, J and Skowronski, J and Emerman, M (2013) Evolutionary Toggling of Vpx/Vpr Specificity Results in Divergent Recognition of the Restriction Factor SAMHD1. PLoS Pathogens, 9 (7). ISSN 1553-7366

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Abstract

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. © 2013 Fregoso et al.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Fregoso, OI
Ahn, Jjia12@pitt.eduJIA12
Wang, C
Mehrens, J
Skowronski, J
Emerman, M
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorLuban, JeremyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 1 July 2013
Date Type: Publication
Journal or Publication Title: PLoS Pathogens
Volume: 9
Number: 7
DOI or Unique Handle: 10.1371/journal.ppat.1003496
Schools and Programs: School of Medicine > Structural Biology
Refereed: Yes
ISSN: 1553-7366
Other ID: NLM PMC3715410
PubMed Central ID: PMC3715410
PubMed ID: 23874202
Date Deposited: 16 Aug 2013 20:48
Last Modified: 13 Oct 2017 20:56
URI: http://d-scholarship.pitt.edu/id/eprint/19503

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