The missing link: allostery and catalysis in the anti-viral protein SAMHD1 DOI Creative Commons
E.R. Morris, Ian A. Taylor

Biochemical Society Transactions, Journal Year: 2019, Volume and Issue: 47(4), P. 1013 - 1027

Published: July 11, 2019

Abstract Vertebrate protein SAMHD1 (sterile-α-motif and HD domain containing 1) regulates the cellular dNTP (2′-deoxynucleoside-5′-triphosphate) pool by catalysing hydrolysis of into 2′-deoxynucleoside triphosphate products. As an important regulator cell proliferation a key player in homeostasis, mutations to are implicated hypermutated cancers, germline associated with Chronic Lymphocytic Leukaemia inflammatory disorder Aicardi–Goutières Syndrome. By limiting supply dNTPs for viral DNA synthesis, also restricts replication several retroviruses, such as HIV-1, some viruses dendritic myeloid lineage cells resting T-cells. activity is regulated throughout cycle, both at level expression post-translationally, through phosphorylation. In addition, allosteric regulation further fine-tunes catalytic SAMHD1, nucleotide-activated homotetramer catalytically active form protein. cells, GTP dATP likely physiological activators two adjacent sites, AL1 (GTP) AL2 (dATP), that bridge monomer–monomer interfaces stabilise homotetramer. This review summarises extensive X-ray crystallographic, biophysical molecular dynamics experiments have elucidated features SAMHD1. We present comprehensive mechanism detailing structural components coupling between nucleotide-induced tetramerization catalysis

Language: Английский

SAMHD1 in cancer: curse or cure? DOI Creative Commons
Kerstin Schott,

Catharina Majer,

Alla Bulashevska

et al.

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

Citations

30
USP18 (UBP43) Abrogates p21-Mediated Inhibition of HIV-1 DOI Open Access
Edmund Osei Kuffour, Kerstin Schott, Ananda Ayyappan Jaguva Vasudevan

et al.

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

Citations

36
Retroviral Restriction Factors and Their Viral Targets: Restriction Strategies and Evolutionary Adaptations DOI Creative Commons
Guney Boso, Christine A. Kozak

Microorganisms, Journal Year: 2020, Volume and Issue: 8(12), P. 1965 - 1965

Published: Dec. 11, 2020

The evolutionary conflict between retroviruses and their vertebrate hosts over millions of years has led to the emergence cellular innate immune proteins termed restriction factors as well viral antagonists. Evidence accumulated in last two decades substantially increased our understanding elaborate mechanisms utilized by these inhibit retroviral replication, that either directly block or interfere with pathways hijacked viruses. Analyses complex interactions describe patterns accelerated evolution for acquisition virus-encoded is also mounting many identified inhibition specific have broader antiviral activity against additional other viruses, exposure multiple virus challenges shaped adaptive evolution. In this review, we provide an overview different steps life cycle, describing action, evolution, targets antagonists evolved counter factors.

Language: Английский

Citations

29
SAMHD1 … and Viral Ways around It DOI Creative Commons
Janina Deutschmann, Thomas Gramberg

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

Citations

26
SUMOylation of SAMHD1 at Lysine 595 is required for HIV-1 restriction in non-cycling cells DOI Creative Commons
Charlotte Martinat,

Arthur Cormier,

Joëlle Tobaly-Tapiero

et al.

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

Citations

24
Attenuation of reverse transcriptase facilitates SAMHD1 restriction of HIV-1 in cycling cells DOI Creative Commons

Ming-Han Tsai,

Sarah J. Caswell,

E.R. Morris

et al.

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

Citations

10
HIV capsids: orchestrators of innate immune evasion, pathogenesis and pandemicity DOI
Kate L. Morling, Mohamed ElGhazaly,

R Milne

et al.

Journal of General Virology, Journal Year: 2025, Volume and Issue: 106(1)

Published: Jan. 13, 2025

Human immunodeficiency virus (HIV) is an exemplar virus, still the most studied and best understood a model for mechanisms of viral replication, immune evasion pathogenesis. In this review, we consider earliest stages HIV infection from transport virion contents through cytoplasm to integration genome into host chromatin. We present holistic virus-host interaction during pivotal stage infection. Central process capsid. The last 10 years have seen transformation in way understand capsid structure function. review key discoveries our latest thoughts on as dynamic regulator innate chromatin targeting. also accessory proteins Vpr Vpx because they are incorporated particles where collaborate with capsids manipulate defensive cellular responses argue that effective regulation uncoating immunity define pandemic potential pathogenesis, how comparison different lineages can reveal what makes lentiviruses special.

Language: Английский

Citations

0
dNTP depletion and beyond: the multifaceted nature of SAMHD1-mediated viral restriction DOI Creative Commons
Pak‐Hin Hinson Cheung, Hua Yang, Li Wu

et al.

Journal of Virology, Journal Year: 2025, Volume and Issue: unknown

Published: April 25, 2025

ABSTRACT SAMHD1 is a dNTPase of mammalian cells. In 2011, was found to be host restriction factor against retroviruses through dNTP reduction. Recent research provides evidence that the antiviral mechanisms cannot explained solely by its activity. Instead, versatility SAMHD1-mediated various viruses suggests extend beyond depletion. This explains multifaceted and broad functions play significant role in innate immunity.

Language: Английский

Citations

0
Cross-talk between SUMOylation and ISGylation in response to interferon DOI

Faten El-Asmi,

Francis P. McManus,

Carlos Eduardo Brantis-de-Carvalho

et al.

Cytokine, Journal Year: 2020, Volume and Issue: 129, P. 155025 - 155025

Published: Feb. 7, 2020

Language: Английский

Citations

26
Cell Cycle Regulation in Macrophages and Susceptibility to HIV-1 DOI Creative Commons
Isabella A. T. M. Ferreira, J. Zachary Porterfield, Ravindra K. Gupta

et al.

Viruses, Journal Year: 2020, Volume and Issue: 12(8), P. 839 - 839

Published: July 31, 2020

Macrophages are the first line of defence against invading pathogens. They play a crucial role in immunity but also regeneration and homeostasis. Their remarkable plasticity their phenotypes function provides them with ability to quickly respond environmental changes infection. Recent work shows that macrophages undergo cell cycle transition from G0/terminally differentiated state G1 state. This G0-to-G1 presents window opportunity for HIV-1 an important target express high levels deoxynucleotide-triphosphate hydrolase SAMHD1, which restricts viral DNA synthesis by decreasing dNTPs. While G0 is non-permissive infection, very permissive because switch off antiviral restriction factor SAMHD1 phosphorylation, thereby allowing productive Here, we explore macrophage interplay between its regulation permissivity

Language: Английский

Citations

25