Aicardi-Goutieres Syndrome Gene and HIV-1 Restriction Factor SAMHD1 Is a dGTP-regulated Deoxynucleotide Triphosphohydrolas

Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 11/2011; 286(51):43596-600. DOI: 10.1074/jbc.C111.317628
Source: PubMed

ABSTRACT The SAMHD1 protein is an HIV-1 restriction factor that is targeted by the HIV-2 accessory protein Vpx in myeloid lineage cells. Mutations in the SAMHD1 gene cause Aicardi-Goutières syndrome, a genetic disease that mimics congenital viral infection. To determine the physiological function of the SAMHD1 protein, the SAMHD1 gene was cloned, recombinant protein was produced, and the catalytic activity of the purified enzyme was identified. We show that SAMHD1 contains a dGTP-regulated deoxynucleotide triphosphohydrolase. We propose that Vpx targets SAMHD1 for degradation in a viral strategy to control cellular deoxynucleotide levels for efficient replication.

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    • "T . E . White et al . / Virology 460 - 461 ( 2014 ) 34 – 44 38 ( Goldstone et al . , 2011 ; Kim et al . , 2012 ; Lahouassa et al . , 2012 ; Powell et al . , 2011 ; White et al . , 2013a ) . To test whether the different human SAMHD1 proteins are affected on their ability to decrease the cellular levels of dNTPs , we measured the levels of dATP , dTTP and dGTP in U937 cells stably expressing the different human SAMHD1 polymorphisms . As shown in Fig . 8 , all tested human SAMHD1 polymorphisms wer"
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    ABSTRACT: 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.
    Virology 07/2014; 460(461):34-44. DOI:10.1016/j.virol.2014.04.023 · 3.35 Impact Factor
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    • "). SAMHD1 is a 626 amino acid protein that consists of an amino-terminal SAM domain, a central HD domain and a C-terminal uncharacterized domain (Li et al., 2000; Liao et al., 2008). SAMHD1 is a deoxynucleoside-triphosphate (dNTP) phosphohydrolase (Goldstone et al., 2011; Powell et al., 2011; Yan et al., 2013), which reduces the pool of dNTPs available for reverse transcription both in myeloid cells (Lahouassa et al., 2012; "
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    ABSTRACT: Vpx is a protein encoded by members of the HIV-2/SIVsmm and SIVrcm/SIVmnd-2 lineages of primate lentiviruses, and is packaged into viral particles. Vpx plays a critical role during the early steps of the viral life cycle and has been shown to counteract SAMHD1, a restriction factor in myeloid and resting T cells. However, it is becoming evident that Vpx is a multifunctional protein in that SAMHD1 antagonism is likely not its sole role. This review summarizes the current knowledge on this X-traordinary protein.
    Frontiers in Microbiology 04/2014; 5:126. DOI:10.3389/fmicb.2014.00126 · 3.94 Impact Factor
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    • "In contrast, LINE-1 inhibition by SAMHD1 is observed in dividing cells. SAMHD1's dNTPase activity depends on residues H167, H206, D207, and D311 within the HD domain (Aravind and Koonin, 1998; Goldstone et al., 2011; Powell et al., 2011) and is crucial for retroviral inhibition because mutations at H206/D207 compromise both enzymatic activity and antiviral potency (Kim et al., 2012; Laguette et al., 2011; Lahouassa et al., 2012). However, in our study, the D311A mutation, which depletes the hydrolase activity of SAMHD1 (Goldstone et al., 2011), still functions as a LINE-1 inhibitor. "
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    ABSTRACT: Long interspersed elements 1 (LINE-1) occupy at least 17% of the human genome and are its only active autonomous retrotransposons. However, the host factors that regulate LINE-1 retrotransposition are not fully understood. Here, we demonstrate that the Aicardi-Goutières syndrome gene product SAMHD1, recently revealed to be an inhibitor of HIV/simian immunodeficiency virus (SIV) infectivity and neutralized by the viral Vpx protein, is also a potent regulator of LINE-1 and LINE-1-mediated Alu/SVA retrotransposition. We also found that mutant SAMHD1s of Aicardi-Goutières syndrome patients are defective in LINE-1 inhibition. Several domains of SAMHD1 are critical for LINE-1 regulation. SAMHD1 inhibits LINE-1 retrotransposition in dividing cells. An enzymatic active site mutant SAMHD1 maintained substantial anti-LINE-1 activity. SAMHD1 inhibits ORF2p-mediated LINE-1 reverse transcription in isolated LINE-1 ribonucleoproteins by reducing ORF2p level. Thus, SAMHD1 may be a cellular regulator of LINE-1 activity that is conserved in mammals.
    Cell Reports 09/2013; 4(6). DOI:10.1016/j.celrep.2013.08.019 · 8.36 Impact Factor
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