Antagonism of SAMHD1 is actively maintained in natural infections of simian immunodeficiency virus

Spragg, Chelsea; Emerman, Michael

doi:10.1073/pnas.1316839110

Cited by 29 publications

(45 citation statements)

References 32 publications

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“…In addition to cell cycle arrest, several SIV Vpr alleles are capable of targeting the host restriction factor SAMHD1 and that function became separated in the sooty mangabey SIV (SIVsm) lineage upon duplication to generate the vpx gene peculiar to this group (7). Importantly, at present HIV-1 Vpr is not known to retain any SAMHD1 counteractivity (7)(8)(9)(10).…”

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confidence: 99%

G ₂ /M Cell Cycle Arrest Correlates with Primate Lentiviral Vpr Interaction with the SLX4 Complex

Berger

Lawrence

Hué

et al. 2015

J Virol

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V iral protein R (Vpr) is an accessory protein common to all primate lentiviruses whose role in viral replication remains unclear. It is packaged specifically into virions and is associated with the reverse-transcription complex during early steps of infection (1, 2). Although implicated in various virological processes, the major phenotype ascribed to Vpr is the induction of G 2 /M cell cycle arrest in dividing cells (3, 4). The importance of this phenotype in human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) replication has been notoriously difficult to define because of the minor effects of its deletion on viral replication in cell culture (5). However, reversion of inactivating mutations in both primates and humans highlights that Vpr plays an essential role for viral replication in vivo (6). In addition to cell cycle arrest, several SIV Vpr alleles are capable of targeting the host restriction factor SAMHD1 and that function became separated in the sooty mangabey SIV (SIVsm) lineage upon duplication to generate the vpx gene peculiar to this group (7). Importantly, at present HIV-1 Vpr is not known to retain any SAMHD1 counteractivity (7-10).Vpr-mediated cell cycle arrest depends on its localization to nuclear compartments and the ability to hijack a Cullin-4/DDB1/ Roc1 E3 ubiquitin ligase complex through the WD-containing DCAF-1 adaptor (11,12). For HIV-1 Vpr, this leads ultimately to the activation of the ataxia telangiectasia M and Rad3-related (ATR) and Chk1 kinases to prevent cell cycle progression into mitosis (13). Although several putative Vpr targets have been described, the identity of that which triggers this event has until recently remained elusive. The requirement for the ubiquitin-proteasome system and, in particular, K48-ubiquitin linkages supported a notion that the Vpr target is degraded (14). However, Laguette and colleagues recently found that Vpr interacts with the SLX4 complex, members of the Fanconi anemia DNA repair pathway (15). SLX4, also known as Fanconi anemia complementation group P (FANCP), is a large adaptor protein that acts as a scaffold for a heterodimeric structure-specific endonuclease comprised of MUS81 and EME1. This interaction directs this endonuclease and

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confidence: 99%

G ₂ /M Cell Cycle Arrest Correlates with Primate Lentiviral Vpr Interaction with the SLX4 Complex

Berger

Lawrence

Hué

et al. 2015

J Virol

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“…Vpx proteins of these two SIV lineages have adopted different strategies to recognize SAMHD1. The different modes of these interactions are probably a result of evolutionary toggling due to the head-tail conformation of SAMHD1 [22,23]. In contrast, Vpx of SIVmnd2 binds to the N-terminal domain (NtD) of mandrill SAMHD1 [21,22].…”

Section: Introductionmentioning

confidence: 99%

“…Helix 1 (amino acids[21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] − indicates non-statistically significant changes in SAMHD1 level.…”

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confidence: 99%

Characterization of the interactions between SIVrcm Vpx and red-capped mangabey SAMHD1

et al. 2015

Biochemical Journal

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SAMHD1 (SAM domain- and HD domain-containing protein 1) inhibits HIV-1 infection of myeloid cells and resting CD4+ T-cells. Two lineages of primate lentiviruses, the sooty mangabey SIV (simian immunodeficiency virus) (SIVsm)/macaque SIV (SIVmac)/HIV-2 lineage and the red-capped mangabey SIV (SIVrcm) lineage, carry a SAMHD1 antagonist called Vpx. Vpx recognizes SAMHD1 and recruits a ubiquitin E3 ligase complex that is composed of CUL4 (Cullin4), DDB1 (damaged DNA-binding protein 1) and a member of the DCAF (DDB1/CUL4-associated factor) family called DCAF1. This E3 ligase complex polyubiquitinates SAMHD1, which leads to proteasomal degradation of SAMHD1. As opposed to the well-characterized interaction of SIVmac Vpx with human SAMHD1 and DCAF1, SIVrcm Vpx adopts a different mode of interaction with SAMHD1 of red-capped mangabeys. In the present study, we have characterized the interactions that are essential for SIVrcm Vpx-mediated degradation of rcmSAMHD1 (red-capped mangabey SAMHD1). Using mutagenesis and molecular modelling, we have determined the key role of the W23LHR26 peptide of SIVrcm Vpx in recognizing rcmSAMHD1. The amino acids Phe15, Leu36, Phe52, Arg55 and Arg56 at the N-terminal domain (NtD) of rcmSAMHD1 are involved in interaction with Vpxrcm (red-capped mangabey Vpx). The molecular model of rcmSAMHD1-NtD, Vpxrcm and C-terminal domain (CtD) of DCAF1 (DCAF1-CtD) complex reveals further that rcmSAMHD1-NtD and Vpxrcm utilize an interaction interface that is different from that used by human SAMHD1-CtD and Vpxsm. These findings provide further insights into the different modes of interaction between Vpx and SAMHD1 as the result of the 'arms race' of virus and host cell.

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“…Efficient infection of human primary macrophages, dendritic cells and resting CD4 + T-cells by simian immunodeficiency virus (SIV mac ) requires the accessory protein Vpx (Arfi et al, 2008; Baldauf et al, 2012; Descours et al, 2012; Goujon et al, 2008; Goujon et al, 2003; Goujon et al, 2007; Spragg and Emerman, 2013). Vpx is essential for both SIV infection of primary macrophages and viral pathogenesis in vivo (Belshan et al, 2006; Fletcher et al, 1996; Gibbs et al, 1995; Hirsch et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Effects of human SAMHD1 polymorphisms on HIV-1 susceptibility

et al. 2014

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SAMHD1 is a human restriction factor that prevents efficient infection of macrophages, dendritic cells and resting CD4+ T cells by HIV-1. Here we explored the antiviral activity and biochemical properties of human SAMHD1 polymorphisms. Our studies focused on human SAMHD1 polymorphisms that were previously identified as evolving under positive selection for rapid amino acid replacement during primate speciation. The different human SAMHD1 polymorphisms were tested for their ability to block HIV-1, HIV-2 and equine infectious anemia virus (EIAV). All studied SAMHD1 variants block HIV-1, HIV-2 and EIAV infection when compared to wild type. We found that these variants did not lose their ability to oligomerize or to bind RNA. Furthermore, all tested variants were susceptible to degradation by Vpx, and localized to the nuclear compartment. We tested the ability of human SAMHD1 polymorphisms to decrease the dNTP cellular levels. In agreement, none of the different SAMHD1 variants lost their ability to reduce cellular levels of dNTPs. Finally, we found that none of the tested human SAMHD1 polymorphisms affected the ability of the protein to block LINE-1 retrotransposition.

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Antagonism of SAMHD1 is actively maintained in natural infections of simian immunodeficiency virus

Cited by 29 publications

References 32 publications

G ₂ /M Cell Cycle Arrest Correlates with Primate Lentiviral Vpr Interaction with the SLX4 Complex

G ₂ /M Cell Cycle Arrest Correlates with Primate Lentiviral Vpr Interaction with the SLX4 Complex

Characterization of the interactions between SIVrcm Vpx and red-capped mangabey SAMHD1

Effects of human SAMHD1 polymorphisms on HIV-1 susceptibility

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Antagonism of SAMHD1 is actively maintained in natural infections of simian immunodeficiency virus

Cited by 29 publications

References 32 publications

G 2 /M Cell Cycle Arrest Correlates with Primate Lentiviral Vpr Interaction with the SLX4 Complex

G 2 /M Cell Cycle Arrest Correlates with Primate Lentiviral Vpr Interaction with the SLX4 Complex

Characterization of the interactions between SIVrcm Vpx and red-capped mangabey SAMHD1

Effects of human SAMHD1 polymorphisms on HIV-1 susceptibility

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G ₂ /M Cell Cycle Arrest Correlates with Primate Lentiviral Vpr Interaction with the SLX4 Complex

G ₂ /M Cell Cycle Arrest Correlates with Primate Lentiviral Vpr Interaction with the SLX4 Complex