Tight Interplay among SAMHD1 Protein Level, Cellular dNTP Levels, and HIV-1 Proviral DNA Synthesis Kinetics in Human Primary Monocyte-derived Macrophages

Kim, Baek; Nguyen, Laura A.; Daddacha, Waaqo; Hollenbaugh, Joseph A.

doi:10.1074/jbc.c112.374843

Cited by 185 publications

(268 citation statements)

References 36 publications

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“…Through this viral protein, two cellular restriction factors whose antiviral activity seems mostly specific to human myeloid cells have been described so far: the apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3A member (APOBEC3A or A3A) and the sterile ␣ motif-hydroxylase domain 1 protein (SAMHD1) (9 -13). More specifically, SAMHD1 has been recently shown to restrict lentiviral infection by diminishing the pool of intracellular dNTPs (14,15), providing a molecular explanation for previous observations indicating that myeloid cells infection was inefficient because of low dNTPs concentrations (16 -18).…”

Section: Samhd1 Is a Newly Identified Restriction Factor That Targetsmentioning

confidence: 77%

Functional Analysis of the Relationship between Vpx and the Restriction Factor SAMHD1

Berger

Turpin

Cordeil

et al. 2012

Journal of Biological Chemistry

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Background: SAMHD1 is a novel antiviral factor counteracted by the viral protein Vpx Results:Several residues in Vpx affect its ability to increase infection and degrade SAMHD1. Conclusion:Vpx functionality correlates with SAMHD1 degradation, but not with Vpx stability and Vpx-Vpx association. Significance:Several mutants provide further insights into the molecular mechanism of Vpx-induced protection.

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Section: Samhd1 Is a Newly Identified Restriction Factor That Targetsmentioning

confidence: 77%

Functional Analysis of the Relationship between Vpx and the Restriction Factor SAMHD1

Berger

Turpin

Cordeil

et al. 2012

Journal of Biological Chemistry

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“…Previously, we have shown that dNTP levels in macrophage are lower than the K m values of RT (4,50). However, Vpx-mediated degradation of SAMHD1 elevates dNTP levels above the K m values of RT (5,50), accelerating proviral DNA synthesis (46). Therefore, we further envision that Vpx-induced dNTP elevation in the non-dividing target cell types enables RTs to effectively overcome the rNMP-induced pausing as shown in Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, we also reported that HIV-2 and some SIVs encode an accessory protein, Vpx, that antagonizes the anti-viral function of SAMHD1 by proteasomal degradation. This led to the elevation of cellular dNTPs in macrophages (5,46), dendritic cells (47), and resting T cells (48,49), which ultimately rescued the delayed reverse transcription process. Previously, we have shown that dNTP levels in macrophage are lower than the K m values of RT (4,50).…”

Section: Discussionmentioning

confidence: 99%

Effect of Ribonucleotides Embedded in a DNA Template on HIV-1 Reverse Transcription Kinetics and Fidelity

Daddacha

Noble²,

Nguyen

et al. 2013

Journal of Biological Chemistry

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Background: Under limiting dNTP concentrations, HIV-1 RT incorporates rNTPs during DNA synthesis. Results: HIV-1 RT utilizes dNTP less efficiently around rNMPs, and mismatch extension fidelity is significantly reduced. Conclusion: Presence of an rNMP in DNA template slows HIV-1 RT-mediated DNA synthesis and reduces fidelity. Significance: This study provides insight into how rNMP incorporation during proviral DNA synthesis can affect HIV-1 replication kinetics and fidelity.

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“…It has recently been identified as a restriction factor that blocks infection by a broad range of retroviruses, including HIV-1, in noncycling myeloid-lineage cells and quiescent CD4 + T lymphocytes (2-7). The dNTPase activity of SAMHD1 depletes the cellular dNTP pool, inhibiting the reverse transcription of the viral RNA genome (8)(9)(10). SAMHD1 was also found to inhibit infection by certain DNA viruses including herpes simplex virus type 1 (HSV-1) and vaccinia virus in nondividing macrophages (11,12).…”

mentioning

confidence: 99%

Structural basis of cellular dNTP regulation by SAMHD1

Tang

Zhao

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

117

204

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The sterile alpha motif and HD domain-containing protein 1 (SAMHD1), a dNTPase, prevents the infection of nondividing cells by retroviruses, including HIV, by depleting the cellular dNTP pool available for viral reverse transcription. SAMHD1 is a major regulator of cellular dNTP levels in mammalian cells. Mutations in SAMHD1 are associated with chronic lymphocytic leukemia (CLL) and the autoimmune condition Aicardi Goutières syndrome (AGS). The dNTPase activity of SAMHD1 can be regulated by dGTP, with which SAMHD1 assembles into catalytically active tetramers. Here we present extensive biochemical and structural data that reveal an exquisite activation mechanism of SAMHD1 via combined action of both GTP and dNTPs. We obtained 26 crystal structures of SAMHD1 in complex with different combinations of GTP and dNTP mixtures, which depict the full spectrum of GTP/dNTP binding at the eight allosteric and four catalytic sites of the SAMHD1 tetramer. Our data demonstrate how SAMHD1 is activated by binding of GTP or dGTP at allosteric site 1 and a dNTP of any type at allosteric site 2. Our enzymatic assays further reveal a robust regulatory mechanism of SAMHD1 activity, which bares resemblance to that of the ribonuclease reductase responsible for cellular dNTP production. These results establish a complete framework for a mechanistic understanding of the important functions of SAMHD1 in the regulation of cellular dNTP levels, as well as in HIV restriction and the pathogenesis of CLL and AGS.HIV restriction factor | dNTP metabolism | tetramerization | triphosphohydrolase | allosteric regulation S AMHD1 is a dNTPase that hydrolyzes dNTPs into deoxyribonucleosides (dNs) and triphosphates (1). It has recently been identified as a restriction factor that blocks infection by a broad range of retroviruses, including HIV-1, in noncycling myeloid-lineage cells and quiescent CD4 + T lymphocytes (2-7). The dNTPase activity of SAMHD1 depletes the cellular dNTP pool, inhibiting the reverse transcription of the viral RNA genome (8-10). SAMHD1 was also found to inhibit infection by certain DNA viruses including herpes simplex virus type 1 (HSV-1) and vaccinia virus in nondividing macrophages (11,12). Apart from viral restriction, SAMHD1 is ubiquitously expressed in both differentiated and undifferentiated cells of various human organs (2, 13), where it functions in the regulation of DNA damage signaling and proper activation of the innate immune response (14, 15). Mutations in SAMHD1, many of which result in deficiency in the dNTPase activity, are associated with chronic lymphocytic leukemia (CLL) (15, 16) and the autoimmune condition AicardiGoutieres syndrome (AGS) (17, 18).It has been recognized that SAMHD1 may play an important role in the regulation of cellular dNTP levels, which are critical to the fidelity of DNA synthesis and the stability of the genome (13). Abnormal size and/or the imbalance of the dNTP pool may activate the S-phase checkpoint for cell cycle arrest (19,20). In mammalian cells, the concentration of cellular dNT...

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Tight Interplay among SAMHD1 Protein Level, Cellular dNTP Levels, and HIV-1 Proviral DNA Synthesis Kinetics in Human Primary Monocyte-derived Macrophages

Cited by 185 publications

References 36 publications

Functional Analysis of the Relationship between Vpx and the Restriction Factor SAMHD1

Functional Analysis of the Relationship between Vpx and the Restriction Factor SAMHD1

Effect of Ribonucleotides Embedded in a DNA Template on HIV-1 Reverse Transcription Kinetics and Fidelity

Structural basis of cellular dNTP regulation by SAMHD1

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