p21 Restricts HIV-1 in Monocyte-Derived Dendritic Cells through the Reduction of Deoxynucleoside Triphosphate Biosynthesis and Regulation of SAMHD1 Antiviral Activity DOI Open Access
José Carlos Valle‐Casuso, Awatef Allouch,

Annie David

et al.

Journal of Virology, Journal Year: 2017, Volume and Issue: 91(23)

Published: Sept. 21, 2017

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

Language: Английский

SAMHD1 shapes deoxynucleotide triphosphate homeostasis by interconnecting the depletion and biosynthesis of different dNTPs DOI Creative Commons
Claudia McCown, Corey H. Yu, Dmitri N. Ivanov

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 17, 2025

SAMHD1 is a dNTPase that impedes replication of HIV-1 in myeloid cells and resting T lymphocytes. Here we elucidate the substrate activation mechanism SAMHD1, which involves dNTP binding at allosteric sites transient tetramerization. Our findings reveal tetramerization alone insufficient to promote hydrolysis; instead, requires an inactive tetrameric intermediate with partially occupied sites. The equilibrium between active states regulates activity, driven by dissociation additional ligands preassembled tetramer. Furthermore, catalytic efficiency, but not specificity, modulated identity dNTPs occupying We show how this regulation shapes deoxynucleotide homeostasis balancing production SAMHD1-catalyzed depletion. Notably, exhibits distinct functionality, term facilitated depletion, whereby increased biosynthesis certain enhances depletion others. regulatory relationship different sheds light on emerging role biology implications for HIV/AIDS, innate antiviral immunity, cell disorders, telomere maintenance therapeutic efficacy nucleoside analogs.

Language: Английский

Citations

3
Deoxyribonucleotide metabolism, mutagenesis and cancer DOI

Christopher K. Mathews

Nature reviews. Cancer, Journal Year: 2015, Volume and Issue: 15(9), P. 528 - 539

Published: Aug. 24, 2015

Language: Английский

Citations

177
SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia DOI

Constanze Schneider,

Thomas Oellerich, Hanna‐Mari Baldauf

et al.

Nature Medicine, Journal Year: 2016, Volume and Issue: 23(2), P. 250 - 255

Published: Dec. 19, 2016

Language: Английский

Citations

149
SAMHD1 Functions and Human Diseases DOI Creative Commons
Si’Ana A. Coggins, Bijan Mahboubi, Raymond F. Schinazi

et al.

Viruses, Journal Year: 2020, Volume and Issue: 12(4), P. 382 - 382

Published: March 31, 2020

Deoxynucleoside triphosphate (dNTP) molecules are essential for the replication and maintenance of genomic information in both cells a variety viral pathogens. While process dNTP biosynthesis by cellular enzymes, such as ribonucleotide reductase (RNR) thymidine kinase (TK), has been extensively investigated, negative regulatory mechanism pools was recently found to involve sterile alpha motif (SAM) domain histidine-aspartate (HD) domain-containing protein 1, SAMHD1. When active, triphosphohydrolase activity SAMHD1 degrades dNTPs into their 2'-deoxynucleoside (dN) subparts, steadily depleting intercellular pools. The differential expression levels activation states various cell types contributes unique that either aid (i.e., dividing T cells) or restrict nondividing macrophages) consumes dNTPs. Genetic mutations induce rare inflammatory encephalopathy called Aicardi-Goutières syndrome (AGS), which phenotypically resembles infection. Recent publications have identified diverse roles double-stranded break repair, genome stability, stress response through interferon signaling. Finally, series were also reported cancer while why is mutated these remains investigated. Here, we reviewed studies begun illuminating highly virology, immunology, biology.

Language: Английский

Citations

82
CyclinA2-Cyclin-dependent Kinase Regulates SAMHD1 Protein Phosphohydrolase Domain DOI Creative Commons

Junpeng Yan,

Caili Hao,

Maria DeLucia

et al.

Journal of Biological Chemistry, Journal Year: 2015, Volume and Issue: 290(21), P. 13279 - 13292

Published: April 7, 2015

Language: Английский

Citations

90
Low dNTP levels are necessary but may not be sufficient for lentiviral restriction by SAMHD1 DOI Creative Commons
Sarah Welbourn, Klaus Strebel

Virology, Journal Year: 2015, Volume and Issue: 488, P. 271 - 277

Published: Dec. 4, 2015

Language: Английский

Citations

59
Dendritic Cells, the Double Agent in the War Against HIV-1 DOI Creative Commons

Alba Martín-Moreno,

María Ángeles Muñoz‐Fernández

Frontiers in Immunology, Journal Year: 2019, Volume and Issue: 10

Published: Oct. 23, 2019

Human Immunodeficiency Virus (HIV) infects cells from the immune system and has thus developed tools to circumvent host immunity use it in its advance. Dendritic (DCs) are first encounter HIV, being main antigen (Ag) presenting cells, they link innate adaptive responses. While DCs work promote an efficient response halt infection, HIV-1 ways take advantage of their role uses gain faster more access CD4+ T cells. Due ability activate a specific response, promising candidates achieve functional cure but knowing molecular partakers that determine relationship between virus cell is key for rational successful design DC-based therapy. In this review, we summarize current state knowledge on how both DC subsets (myeloid plasmacytoid DCs) act presence HIV-1, focus different pathways can after binding DC. First, explore consequences recognition by each receptor DCs, including CD4 DC-SIGN. Second, look at cellular mechanisms prevent productive infection weapons turn defense into Trojan horse hides all way cell. Finally, discuss possible outcomes DC-T contact.

Language: Английский

Citations

54
Effects of T592 phosphomimetic mutations on tetramer stability and dNTPase activity of SAMHD1 can not explain the retroviral restriction defect DOI Creative Commons
Akash Bhattacharya, Zhonghua Wang,

Tommy E. White

et al.

Scientific Reports, Journal Year: 2016, Volume and Issue: 6(1)

Published: Aug. 11, 2016

Abstract SAMHD1, a dNTP triphosphohydrolase, contributes to interferon signaling and restriction of retroviral replication. SAMHD1-mediated is thought result from the depletion cellular pools, but it remains controversial whether dNTPase activity SAMHD1 sufficient for restriction. The ability regulated in cells by phosphorylation on T592. Phosphomimetic mutations T592 are not competent, appear intact their deplete dNTPs. Here we use analytical ultracentrifugation, fluorescence polarization NMR-based enzymatic assays investigate impact phosphomimetic tetramerization vitro . We find that affect kinetics tetramer assembly disassembly, effects equilibrium insignificant. In contrast, Y146S/Y154S dimerization-defective mutant displays severe defect , indistinguishable WT its pools restrict HIV Our data suggest effect likely explain hypothesize subject additional regulatory mechanisms have yet been recapitulated

Language: Английский

Citations

53
HIV suppression by host restriction factors and viral immune evasion DOI
Xiaofei Jia, Qi Zhao, Yong Xiong

et al.

Current Opinion in Structural Biology, Journal Year: 2015, Volume and Issue: 31, P. 106 - 114

Published: April 1, 2015

Language: Английский

Citations

51
Ribonucleotide reductase inhibitors suppress SAMHD 1 ara‐ CTP ase activity enhancing cytarabine efficacy DOI Creative Commons
Sean G. Rudd,

Nikolaos Tsesmetzis,

Kumar Sanjiv

et al.

EMBO Molecular Medicine, Journal Year: 2020, Volume and Issue: 12(3)

Published: Jan. 17, 2020

The deoxycytidine analogue cytarabine (ara-C) remains the backbone treatment of acute myeloid leukaemia (AML) as well other haematological and lymphoid malignancies, but must be combined with chemotherapeutics to achieve cure. Yet, underlying mechanism dictating synergistic efficacy combination chemotherapy largely unknown. dNTPase SAMHD1, which regulates dNTP homoeostasis antagonistically ribonucleotide reductase (RNR), limits ara-C by hydrolysing active triphosphate metabolite ara-CTP. Here, we report that clinically used inhibitors RNR, such gemcitabine hydroxyurea, overcome SAMHD1-mediated barrier in primary blasts mouse models AML, displaying SAMHD1-dependent synergy ara-C. We present evidence this is mediated pool imbalances leading allosteric reduction SAMHD1 ara-CTPase activity. Thus, constitutes a novel biomarker for therapies RNR immediate consequences clinical practice improve AML.

Language: Английский

Citations

43