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
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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Item Type: |
Article
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Status: |
Published |
Creators/Authors: |
Creators | Email | Pitt Username | ORCID |
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Fregoso, OI | | | | Ahn, J | jia12@pitt.edu | JIA12 | | Wang, C | | | | Mehrens, J | | | | Skowronski, J | | | | Emerman, M | | | |
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Contributors: |
Contribution | Contributors Name | Email | Pitt Username | ORCID |
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Editor | Luban, Jeremy | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED |
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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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