title: Evolutionary toggling of Vpx/Vpr specificity results in divergent recognition of the restriction factor SAMHD1.
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.
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Oliver I
authors.initials: OI
authors.lastname: Fregoso
authors.forename: Jinwoo
authors.initials: J
authors.lastname: Ahn
authors.forename: Chuanping
authors.initials: C
authors.lastname: Wang
authors.forename: Jennifer
authors.initials: J
authors.lastname: Mehrens
authors.forename: Jacek
authors.initials: J
authors.lastname: Skowronski
authors.forename: Michael
authors.initials: M
authors.lastname: Emerman
mesh_terms: D000818:Animals; D016663:Cercopithecinae; D030562:Databases, Protein; D019143:Evolution, Molecular; D057809:HEK293 Cells; D015498:HIV-2 / Q000235:genetics / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D008954:Models, Biological; D020559:Monomeric GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010802:Phylogeny; D046988:Proteasome Endopeptidase Complex; D054730:Protein Interaction Domains and Motifs; D055550:Protein Stability; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D000076106:SAM Domain and HD Domain-Containing Protein 1; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination; D054334:Viral Regulatory and Accessory Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000737:chemistry
chemical_list: D050505:Mutant Proteins; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; C074286:VPX protein, Human immunodeficiency virus 2; C513059:VPX protein, Simian immunodeficiency virus; D054334:Viral Regulatory and Accessory Proteins; D054325:vpr Gene Products, Human Immunodeficiency Virus; C514913:vpr protein, Human immunodeficiency virus 2; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D046988:Proteasome Endopeptidase Complex; D020559:Monomeric GTP-Binding Proteins