Restriction of diverse retroviruses by SAMHD1

Gramberg, Thomas; Kahle, Tanja; Bloch, Nicolin; Wittmann, Sabine; Müllers, Erik; Daddacha, Waaqo; Hofmann, Henning; Kim, Baek; Lindemann, Dirk; Landau, Nathaniel R.

doi:10.1186/1742-4690-10-26

Cited by 126 publications

(136 citation statements)

References 46 publications

(55 reference statements)

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“…Several findings further support this mechanism. SAMHD1 restricts a wide range of retroviruses, with the exception of foamy virus, which reverse transcribes prior to infection (26). SAMHD1 also restricts vaccinia virus and herpes simplex virus (35), DNA viruses that rely on the cellular dNTP pool for DNA synthesis.…”

Section: Discussionmentioning

confidence: 99%

“…The medium and cytokines were replaced every other day. U937 cells that stably express hemagglutinin (HA)-tagged SAMHD1 (U937-HA.SAMHD1) and THP1 cells that stably express SAMHD1 small hairpin RNA (shRNA) (THP1-SAMHD1.shRNA) have been described previously (17,26). HeLa cells stably expressing Flag-/HAtagged SAMHD1 were generated by transduction of HeLa cells with pOZ.F/H.SAMHD1 (3).…”

Section: Methodsmentioning

confidence: 99%

“…The drug forms an adduct with Nedd8 that prevents the formation of Nedd8-adenylate (25). The MLN4924-Nedd8 adduct binds to NAE but cannot form the thioester bond, preventing cullin neddylation.SAMHD1 was proposed to restrict the replication of diverse retroviruses by diminishing the pool of intracellular dNTPs to a level below that which is required to support reverse transcription, based on several lines of evidence (6,7,15,26,27). The expression of SAMHD1 in differentiated U937 cells reduced dNTP levels by nearly 100-fold, and the addition of exogenous dN partially alleviated the restriction (7).…”

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confidence: 99%

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Inhibition of CUL4A Neddylation Causes a Reversible Block to SAMHD1-Mediated Restriction of HIV-1

Hofmann

Norton

Schultz

et al. 2013

J Virol

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The deoxynucleoside triphosphohydrolase SAMHD1 restricts retroviral replication in myeloid cells. Human immunodeficiency virus type 2 (HIV-2) and a simian immunodeficiency virus from rhesus macaques (SIVmac) encode Vpx, a virion-packaged accessory protein that counteracts SAMHD1 by inducing its degradation. SAMHD1 is thought to work by depleting the pool of intracellular deoxynucleoside triphosphates but has also been reported to have exonuclease activity that could allow it to degrade the viral genomic RNA or viral reverse-transcribed DNA. To induce the degradation of SAMHD1, Vpx co-opts the cullin4a-based E3 ubiquitin ligase, CRL4. E3 ubiquitin ligases are regulated by the covalent attachment of the ubiquitin-like protein Nedd8 to the cullin subunit. Neddylation can be prevented by MLN4924, a drug that inhibits the nedd8-activating enzyme. We report that MLN4924 inhibits the neddylation of CRL4, blocking Vpx-induced degradation of SAMHD1 and maintaining the restriction. Removal of the drug several hours postinfection released the block. Similarly, Vpx-containing virus-like particles and deoxynucleosides added to the cells more than 24 h postinfection released the SAMHD1-mediated block. Taken together, these findings support deoxynucleoside triphosphate pool depletion as the primary mechanism of SAMHD1 restriction and argue against a nucleolytic mechanism, which would not be reversible. Mammalian cells express antiviral proteins that restrict the replication of viruses like HIV-1 and other lentiviruses. One such restriction factor is SAMHD1, a deoxynucleoside triphosphohydrolase that blocks retrovirus infection at reverse transcription in nondividing myeloid cells, such as macrophages and dendritic cells (1-3). SAMHD1 is also expressed in T cells, where it blocks the infection of resting T cells but has little effect on activated T cells (4, 5). It is thought to work by depleting the pool of intracellular deoxynucleoside (dN) triphosphates (dNTPs) to a level below that which supports reverse transcription (1-3, 6, 7), although other mechanisms have been proposed (8, 9). Viruses have evolved various means of counteracting antiviral host proteins, most notably by encoding accessory proteins (reviewed in reference 10). Lentiviruses, such as human immunodeficiency virus type 2 (HIV-2) and a simian immunodeficiency virus from rhesus macaques (SIVmac), encode Vpx, a virion-packaged accessory protein that is released into the target cell postentry (11). Upon its release, Vpx associates with the E3 ubiquitin ligase CRL4 and recruits SAMHD1 to the complex, inducing its proteasomal degradation (12-14). The degradation of SAMHD1 and subsequent rise in dNTP levels occur within 8 h postinfection, after which reverse transcription resumes (15). SAMHD1 localizes to the nucleus of the cell by an amino-terminal nuclear localization sequence (16,17). Deletion of the nuclear localization sequence relocalizes SAMHD1 to the cytoplasm and causes it to be resistant to Vpx-induced degradation. The treatment of cells with leptomycin B,...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Inhibition of CUL4A Neddylation Causes a Reversible Block to SAMHD1-Mediated Restriction of HIV-1

Hofmann

Norton

Schultz

et al. 2013

J Virol

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“…[18][19][20] The block extends to retroviruses in general 21,22 and to other DNA-dependent viruses. 23 SAMHD1 also blocks the infection of resting T cells but not activated CD4 + T cells 24,25 or other cycling cells.…”

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confidence: 99%

HIV Type 1 Infection of Plasmacytoid and Myeloid Dendritic Cells Is Restricted by High Levels of SAMHD1 and Cannot be Counteracted by Vpx

Bloch

O’Brien

Norton

et al. 2014

AIDS Research and Human Retroviruses

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“…SAMHD1 is a retroviral restriction factor that is ubiquitously expressed in most human cell types (1)(2)(3)(4)(5)(6). It blocks infection by HIV-1 and certain DNA viruses, such as herpes simplex virus type 1, in non-dividing myeloid-lineage cells and/or quiescent…”

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confidence: 99%

Impaired dNTPase Activity of SAMHD1 by Phosphomimetic Mutation of Thr-592

Tang

et al. 2015

Journal of Biological Chemistry

100

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Background: Phosphorylation of SAMHD1 Thr-592 inhibits its anti-HIV activity. Results: Phosphomimetic mutation T592E of SAMHD1 perturbs SAMHD1 crystal structure, destabilizes SAMHD1 tetramer, and reduces its dNTP triphosphatase (dNTPase) activity. Conclusion: T592E decreases the dNTPase activity of SAMHD1 via destabilizing the catalytically active tetramer. Significance: Structure-induced impairment of SAMHD1 dNTPase activity by T592E suggests a mechanism of the phosphorylation-regulated SAMHD1 antiviral activity.

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Restriction of diverse retroviruses by SAMHD1

Cited by 126 publications

References 46 publications

Inhibition of CUL4A Neddylation Causes a Reversible Block to SAMHD1-Mediated Restriction of HIV-1

Inhibition of CUL4A Neddylation Causes a Reversible Block to SAMHD1-Mediated Restriction of HIV-1

HIV Type 1 Infection of Plasmacytoid and Myeloid Dendritic Cells Is Restricted by High Levels of SAMHD1 and Cannot be Counteracted by Vpx

Impaired dNTPase Activity of SAMHD1 by Phosphomimetic Mutation of Thr-592

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