TLR4-Mediated Pathway Triggers Interferon-Independent G0 Arrest and Antiviral SAMHD1 Activity in Macrophages

Cell Reports, Journal Year: 2020, Volume and Issue: 30(12), P. 3972 - 3980.e5

Published: March 1, 2020

Macrophages exist predominantly in two distinct states, G0 and a G1-like state that is accompanied by phosphorylation of SAMHD1 at T592. Here, we demonstrate Toll-like receptor 4 (TLR4) activation can potently induce arrest antiretroviral activity an interferon (IFN)-independent pathway. This pathway requires TLR4 engagement with TRIF, but not involvement TBK1 or IRF3. Exclusive Myd88 activators are unable to trigger dephosphorylation, demonstrating this also Myd88/nuclear factor κB (NF-κB) independent. The p21 upregulation CDK1 depletion, consistent the observed dephosphorylation Furthermore, show knockdown TLR4-activated blocks HIV-1 infection macrophages specifically via SAMHD1. Together, these data mobilize intrinsic cell anti-viral activating prior IFN secretion, thereby highlighting importance cell-cycle regulation as response pathogen-associated danger signals macrophages.

Language: Английский

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SAMHD1 in cancer: curse or cure?

Journal of Molecular Medicine, Journal Year: 2021, Volume and Issue: 100(3), P. 351 - 372

Published: Sept. 4, 2021

Abstract Human sterile α motif and HD domain-containing protein 1 (SAMHD1), originally described as the major cellular deoxyribonucleoside triphosphate triphosphohydrolase (dNTPase) balancing intracellular deoxynucleotide (dNTP) pool, has come recently into focus of cancer research. As outlined in this review, SAMHD1 been reported to be mutated a variety types expression is dysregulated many cancers. Therefore, regarded tumor suppressor certain tumors. Moreover, it proposed that might fulfill requirements driver gene development or promote so-called mutator phenotype. Besides its role dNTPase, several novel functions have light only recently, including negative regulator innate immune responses facilitator DNA end resection during replication repair. can placed at crossroads various processes. The present review summarizes chemotherapy sensitivity, highlights mutations found types, aims discuss functional consequences well underlying mechanisms dysregulation potentially involved development.

Language: Английский

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CD81 association with SAMHD1 enhances HIV-1 reverse transcription by increasing dNTP levels

Nature Microbiology, Journal Year: 2017, Volume and Issue: 2(11), P. 1513 - 1522

Published: Sept. 1, 2017

Language: Английский

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USP18 (UBP43) Abrogates p21-Mediated Inhibition of HIV-1

Journal of Virology, Journal Year: 2018, Volume and Issue: 92(20)

Published: Aug. 1, 2018

Macrophages and dendritic cells are usually the first point of contact with pathogens, including lentiviruses. Host restriction factors, SAMHD1, mediate innate immune response against these viruses. However, HIV-1 has evolved to circumvent establishes disseminated infection. The cyclin-dependent kinase inhibitor p21, which is involved in differentiation maturation monocytes, blocks replication at reverse transcription step. p21 thought suppress key enzymes dNTP biosynthesis activates SAMHD1 antiviral function. We report here that human USP18 protein a novel factor potentially contributing HIV by blocking function differentiated myeloid cells. downregulates expression, correlates upregulated intracellular levels inactive form SAMHD1. Depletion stabilizes dephosphorylated block replication.

Language: Английский

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Interplay between Intrinsic and Innate Immunity during HIV Infection

Cells, Journal Year: 2019, Volume and Issue: 8(8), P. 922 - 922

Published: Aug. 17, 2019

Restriction factors are antiviral components of intrinsic immunity which constitute a first line defense by blocking different steps the human immunodeficiency virus (HIV) replication cycle. In immune cells, HIV infection is also sensed several pattern recognition receptors (PRRs), leading to type I interferon (IFN-I) and inflammatory cytokines production that upregulate interferon-stimulated genes (ISGs). Several studies suggest link between these two types immunity. Indeed, restriction factors, generally interferon-inducible, able modulate responses. This review highlights recent knowledge interplay inducing defenses. Counteraction this innate viral proteins will be discussed.

Language: Английский

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SAMHD1 … and Viral Ways around It

Viruses, Journal Year: 2021, Volume and Issue: 13(3), P. 395 - 395

Published: March 2, 2021

The SAM and HD domain-containing protein 1 (SAMHD1) is a dNTP triphosphohydrolase that plays crucial role for variety of different cellular functions. Besides balancing intracellular concentrations, facilitating DNA damage repair, dampening excessive immune responses, SAMHD1 has been shown to act as major restriction factor against various virus species. In addition its well-described activity retroviruses such HIV-1, identified reduce the infectivity viruses herpesviruses CMV EBV, poxvirus VACV, or hepadnavirus HBV. While some are efficiently restricted by SAMHD1, others have developed evasion mechanisms antagonize antiviral SAMHD1. Within this review, we summarize functions highlight countermeasures evolved neutralize

Language: Английский

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SUMOylation of SAMHD1 at Lysine 595 is required for HIV-1 restriction in non-cycling cells

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: July 28, 2021

Abstract SAMHD1 is a cellular triphosphohydrolase (dNTPase) proposed to inhibit HIV-1 reverse transcription in non-cycling immune cells by limiting the supply of dNTP substrates. Yet, phosphorylation T592 downregulates antiviral activity, but not its dNTPase function, implying that additional mechanisms contribute viral restriction. Here, we show SUMOylated on residue K595, modification relies presence proximal SUMO-interacting motif (SIM). Loss K595 SUMOylation suppresses restriction activity SAMHD1, even context constitutively active phospho-ablative T592A mutant has no impact depletion. Conversely, artificial fusion SUMO2 non-SUMOylatable inactive variant restores phenotype reversed phosphomimetic T 592 E mutation. Collectively, our observations clearly establish lack cannot fully account for SAMHD1. We find required stimulate dNTPase-independent cells, an effect antagonized cyclin/CDK-dependent cycling cells.

Language: Английский

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Attenuation of reverse transcriptase facilitates SAMHD1 restriction of HIV-1 in cycling cells

Retrovirology, Journal Year: 2023, Volume and Issue: 20(1)

Published: May 1, 2023

Abstract Background SAMHD1 is a deoxynucleotide triphosphohydrolase that restricts replication of HIV-1 in differentiated leucocytes. not restricted cycling cells and it has been proposed this due to phosphorylation at T592 these inactivating the enzymatic activity. To distinguish between theories for how but cells, we analysed effects substitutions on restriction dNTP levels both as well tetramer stability activity vitro. Results We first showed was nuclease then characterised panel mutants divided them into three classes. found subset lost their ability restrict which generally corresponded with decrease and/or Interestingly, no were able WT despite being regulated by retaining hydrolyse dNTPs. Lowering addition hydroxyurea did give rise restriction. Compellingly however, RT reduced affinity dNTPs significantly wild-type mutant U937 Jurkat T-cells. Restriction correlated reverse transcription levels. Conclusions Altogether, amino acid residue 592 strong effect formation and, although simple “on/off” switch, does correlate cells. However, preventing lowering adding enough restore Nonetheless, dNTPs, mediated observe time active capable inhibiting if reduced. This suggests very high prevents

Language: Английский

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A SAMHD1 mutation associated with Aicardi-Goutières syndrome uncouples the ability of SAMHD1 to restrict HIV-1 from its ability to downmodulate type I interferon in humans

Human Mutation, Journal Year: 2017, Volume and Issue: 38(6), P. 658 - 668

Published: Feb. 23, 2017

Mutations in the human SAMHD1 gene are known to correlate with development of Aicardi-Goutières syndrome (AGS), which is an inflammatory encephalopathy that exhibits neurological dysfunction characterized by increased production type I interferon (IFN); this evidence has led concept protein negatively regulates IFN response. Additionally, been shown prevent efficient HIV-1 infection macrophages, dendritic cells, and resting CD4+ T cells. To gain insights on molecular determinants responsible for deregulated IFN, we explored biochemical, cellular, antiviral properties mutants AGS. Most studied AGS exhibit defects ability oligomerize, decrease levels cellular deoxynucleotide triphosphates localize exclusively nucleus, restrict infection. At least half tested variants preserved be degraded lentiviral Vpx, all them interacted RNA. Our investigations revealed variant p.G209S preserve properties, suggesting residue a determinant regulate response patients Overall, our work genetically separated from its HIV-1.

Language: Английский

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The dNTP triphosphohydrolase activity of SAMHD1 persists during S-phase when the enzyme is phosphorylated at T592

Cell Cycle, Journal Year: 2018, Volume and Issue: 17(9), P. 1102 - 1114

Published: May 3, 2018

SAMHD1 is the major catabolic enzyme regulating intracellular concentrations of DNA precursors (dNTPs). The S-phase kinase CDK2-cyclinA phosphorylates at Thr-592. How this modification affects function highly debated. We investigated role endogenous phosphorylation during cell cycle. Thr-592 occurs first G1/S border and removed mitotic exit parallel with Thr-phosphorylations most CDK1 targets. Differential sensitivity to phosphatase inhibitor okadaic acid suggested different involvement PP1 PP2 families dependent upon time turn-over indicates that does not cause rapid protein degradation. Furthermore, influenced size four dNTP pools independently its phosphorylation. Our findings reveal active entire cycle performs an important regulatory by contributing ribonucleotide reductase maintain pool balance for proper replication.

Language: Английский

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