SAMHD1 specifically restricts retroviruses through its RNase activity

Choi, Jong-Su; Ryoo, Jeongmin; Oh, Changhoon; Hwang, Sung-Yeon; Ahn, Kwangseog

doi:10.1186/s12977-015-0174-4

Cited by 70 publications

(67 citation statements)

References 42 publications

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“…This finding raised the possibility that SAMHD1 does not restrict HIV-1 solely by dNTP pool depletion. Previous reports suggested that SAMHD1 has ribonuclease that degrades the viral genomic RNA in an infected cell (6,24). Our findings do not support this possibility.…”

Section: Discussioncontrasting

confidence: 99%

“…The phosphohydrolase and RNase activities have been genetically separated such that mutation at D137A causes the loss of phosphohydrolase activity, whereas mutation at Q548A causes the loss of the RNase activity. Analysis of these mutated enzymes suggested that that restriction requires only the RNase activity (6,24). These issues remain to be resolved, as the nuclease activities have been questioned in subsequent reports (25,26).…”

Section: The Lentiviral Restriction Factor Samhd1mentioning

confidence: 99%

“…Mouse SAMHD1 Does Not Degrade HIV-1 Genomic Viral RNA-Human SAMHD1 has been proposed to restrict HIV-1 replication by inducing the degradation of the viral genomic RNA (6,24). To test whether this might be the case for mouse SAMHD1, we transfected 293T cells with ISF1, ISF1 T634A and T634E, ISF2, human SAMHD1 T592A and T592E, and the catalytically inactive mutant H233A (2, 13).…”

Section: Phosphorylation Of Isf1 At Thr-634 Regulates Its Antiviralmentioning

confidence: 99%

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A Highly Active Isoform of Lentivirus Restriction Factor SAMHD1 in Mouse

Bloch

Gläsker

Sitaram

et al. 2017

Journal of Biological Chemistry

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Edited by Henrik G. DohlmanThe triphosphohydrolase SAMHD1 (sterile ␣ motif and histidine-aspartate domain-containing protein 1) restricts HIV-1 replication in nondividing myeloid cells by depleting the dNTP pool, preventing reverse transcription. SAMHD1 is also reported to have ribonuclease activity that degrades the virus genomic RNA. Human SAMHD1 is regulated by phosphorylation of its carboxyl terminus at Thr-592, which abrogates its antiviral function yet has only a small effect on its phosphohydrolase activity. In the mouse, SAMHD1 is expressed as two isoforms (ISF1 and ISF2) that differ at the carboxyl terminus due to alternative splicing of the last coding exon. In this study we characterized the biochemical and antiviral properties of the two mouse isoforms of SAMHD1. Both are antiviral in nondividing cells. Mass spectrometry analysis showed that SAMHD1 is phosphorylated at several amino acid residues, one of which (Thr-634) is homologous to Thr-592. Phosphomimetic mutation at Thr-634 of ISF1 ablates its antiviral activity yet has little effect on phosphohydrolase activity in vitro. dGTP caused ISF1 to tetramerize, activating its catalytic activity. In contrast, ISF2, which lacks the phosphorylation site, was significantly more active, tetramerized, and was active without added dGTP. Neither isoform nor human SAMHD1 had detectable RNase activity in vitro or affected HIV-1 genomic RNA stability in newly infected cells. These data support a model in which SAMHD1 catalytic activity is regulated through tetramer stabilization by the carboxyl-terminal tail, phosphorylation destabilizing the complexes and inactivating the enzyme. ISF2 may serve to reduce the dNTP pool to very low levels as a means of restricting virus replication. The lentiviral restriction factor SAMHD12 is a dNTP triphosphohydrolase (1, 2) that inhibits the replication of HIV-1 in myeloid cells (3, 4). The enzyme removes the triphosphate groups of dNTPs, preventing the reverse transcription in newly infected cells (5). In addition, SAMHD1 has been proposed to have ribonuclease activity that degrades the viral genomic RNA upon virus entry (6). HIV-2 and some SIVs counteract the restriction by encoding Vpx, a virion-packaged accessory protein that induces the proteasomal degradation of SAMHD1 (3, 4, 7). Other SIVs, such as the SIV of African green monkeys, counteract SAMHD1 through the related accessory protein Vpr (8, 9). Vpx delivery into the cell by virions causes a rapid rise in the intracellular dNTP concentration, relieving the block to reverse transcription and allowing productive infection (5, 10). HIV-1 does not encode Vpx and as a result replicates poorly in dendritic and other myeloid cells. The requirement for Vpx for infection of myeloid cells can be partially replaced in culture by the addition of extracellular deoxynucleosides, which are converted into dNTPs by the salvage pathway (5). In addition, HIV-1 can be genetically modified to package Vpx, allowing it to infect myeloid cells (11,12).The catalytic activity of SAMHD1 is reg...

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Section: Discussioncontrasting

confidence: 99%

Section: The Lentiviral Restriction Factor Samhd1mentioning

confidence: 99%

Section: Phosphorylation Of Isf1 At Thr-634 Regulates Its Antiviralmentioning

confidence: 99%

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A Highly Active Isoform of Lentivirus Restriction Factor SAMHD1 in Mouse

Bloch

Gläsker

Sitaram

et al. 2017

Journal of Biological Chemistry

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“…6), raising the question for its mode of action. Our data support a model in which the positive effects of VprBP for cellular and viral gene expression in infected cells are at least partially exerted via degradation of its binding partner SAMHD1, which is known to deplete cellular dNTP levels and to degrade viral RNA (56,58,77). Indeed, we detected decreased SAMHD1 expression levels during permissive Pan infection (Fig.…”

Section: Functional Validation Of Significant Protein Signatures Bysupporting

confidence: 88%

Quantitative Proteomic Approach Identifies Vpr Binding Protein as Novel Host Factor Supporting Influenza A Virus Infections in Human Cells

Sadewasser

Paki

Eichelbaum

et al. 2017

Molecular & Cellular Proteomics

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Influenza A virus (IAV) infections are a major cause for respiratory disease in humans, which affects all age groups and contributes substantially to global morbidity and mortality. IAV have a large natural host reservoir in avian species. However, many avian IAV strains lack adaptation to other hosts and hardly propagate in humans. While seasonal or pandemic IAV strains replicate efficiently in permissive human cells, many avian IAV cause abortive nonproductive infections in these hosts despite successful cell entry. However, the precise reasons for these differential outcomes are poorly defined. We hypothesized that the distinct course of an IAV infection with a given virus strain is determined by the differential interplay between specific host and viral factors. By using Spike-in SILAC mass spectrometry-based quantitative proteomics we characterized sets of cellular factors whose abundance is specifically

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“…SAMHD1 potentially can block HIV replication through two distinct enzymatic functions. SAMHD1 can degrade viral nucleic acids through its exonuclease activity (19,20) and deplete the intracellular deoxynucleoside triphosphate (dNTP) pool through its dNTP triphosphatase activity (17). The relative contribution of each activity to the inhibition of HIV replication is the subject of intense debate (21,22).…”

mentioning

confidence: 99%

p21 Restricts HIV-1 in Monocyte-Derived Dendritic Cells through the Reduction of Deoxynucleoside Triphosphate Biosynthesis and Regulation of SAMHD1 Antiviral Activity

Valle-Casuso

Allouch

David

et al. 2017

J Virol

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HIV-1 infection of noncycling cells, such as dendritic cells (DCs), is impaired due to limited availability of deoxynucleoside triphosphates (dNTPs), which are needed for HIV-1 reverse transcription. The levels of dNTPs are tightly regulated during the cell cycle and depend on the balance between dNTP biosynthesis and degradation. SAMHD1 potently blocks HIV-1 replication in DCs, although the underlying mechanism is still unclear. SAMHD1 has been reported to be able to degrade dNTPs and viral nucleic acids, which may both hamper HIV-1 reverse transcription. The relative contribution of these activities may differ in cycling and noncycling cells. Here, we show that inhibition of HIV-1 replication in monocyte-derived DCs (MDDCs) is associated with an increased expression of p21cip1/waf, a cell cycle regulator that is involved in the differentiation and maturation of DCs. Induction of p21 in MDDCs decreases the pool of dNTPs and increases the antiviral active isoform of SAMHD1. Although both processes are complementary in inhibiting HIV-1 replication, the antiviral activity of SAMHD1 in our primary cell model appears to be, at least partially, independent of its dNTPase activity. The reduction in the pool of dNTPs in MDDCs appears rather mostly due to a p21-mediated suppression of several enzymes involved in dNTP synthesis (i.e., RNR2, TYMS, and TK-1). These results are important to better understand the interplay between HIV-1 and DCs and may inform the design of new therapeutic approaches to decrease viral dissemination and improve immune responses against HIV-1.IMPORTANCE DCs play a key role in the induction of immune responses against HIV. However, HIV has evolved ways to exploit these cells, facilitating immune evasion and virus dissemination. We have found that the expression of p21, a cyclin-dependent kinase inhibitor involved in cell cycle regulation and monocyte differentiation and maturation, potentially can contribute to the inhibition of HIV-1 replication in monocyte-derived DCs through multiple mechanisms. p21 decreased the size of the intracellular dNTP pool. In parallel, p21 prevented SAMHD1 phosphorylation and promoted SAMHD1 dNTPase-independent antiviral activity. Thus, induction of p21 resulted in conditions that allowed the effective inhibition of HIV-1 replication through complementary mechanisms. Overall, p21 appears to be a key regulator of HIV infection in myeloid cells.

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SAMHD1 specifically restricts retroviruses through its RNase activity

Cited by 70 publications

References 42 publications

A Highly Active Isoform of Lentivirus Restriction Factor SAMHD1 in Mouse

A Highly Active Isoform of Lentivirus Restriction Factor SAMHD1 in Mouse

Quantitative Proteomic Approach Identifies Vpr Binding Protein as Novel Host Factor Supporting Influenza A Virus Infections in Human Cells

p21 Restricts HIV-1 in Monocyte-Derived Dendritic Cells through the Reduction of Deoxynucleoside Triphosphate Biosynthesis and Regulation of SAMHD1 Antiviral Activity

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