SAMHD1 shapes deoxynucleotide triphosphate homeostasis by interconnecting the depletion and biosynthesis of different dNTPs

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

---

SAMHD1 Functions and Human Diseases

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

---

CD4+ T cells facilitate replication of primary HIV-1 strains in macrophages and formation of macrophage internal virus-containing compartments

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

Published: March 25, 2025

ABSTRACT HIV-1 replication in macrophages is highly variable with internal virus accumulation so-called virus-containing compartments (VCCs). VCCs represent a reservoir that shielded from the antiviral immune response. VCC formation has been studied lab-adapted HIV-1, but it not investigated whether primary strains induce VCCs. Furthermore, although transmit to CD4+ T cells, effect of cells on unknown. We analyzed ability and replicate macrophages, non-infected cell coculture, formation. All replicated whereas only efficiently macrophage monocultures. Coculture enhanced process associated increased dependent direct cell-to-cell contact. Broadly neutralizing antibodies differentially affected cell-mediated enhancement macrophages. CD4 antibody treatment phenocopied infection-promoting coculture. In conclusion, facilitate induction appears be proxy for this phenotype. are promoted by CD4- GP120-dependent manner. Our findings highlight critical role cell-macrophage interaction dynamics call strategies interfere order target IMPORTANCE Here, we focus intimate interplay between HIV-1-infected cells. Specifically, (VCCs) within which thought serve as viral sanctuaries reservoirs. Notably, were unable unless they cocultured leading replication. This suggests an essential facilitating data importance addressing latent also targeting achieve ultimate goal functional cure.

Language: Английский

---

The complex biology of human cytomegalovirus latency

Advances in virus research, Journal Year: 2022, Volume and Issue: unknown, P. 31 - 85

Published: Jan. 1, 2022

Language: Английский

---

The Cytomegalovirus Protein Kinase pUL97: Host Interactions, Regulatory Mechanisms and Antiviral Drug Targeting

Microorganisms, Journal Year: 2020, Volume and Issue: 8(4), P. 515 - 515

Published: April 4, 2020

Human cytomegalovirus (HCMV) expresses a variety of viral regulatory proteins that undergo close interaction with host factors including viral-cellular multiprotein complexes. The HCMV protein kinase pUL97 represents cyclin-dependent ortholog (vCDK) determines the efficiency replication via phosphorylation and cellular substrates. A hierarchy functional importance individual pUL97-mediated events has been discussed; however, most pronounced pUL97-dependent phenotype could be assigned to nuclear egress, as illustrated by deletion UL97 gene or pharmacological inhibition. Despite earlier data pointing cyclin-independent functionality, experimental evidence increasingly emphasized role pUL97-cyclin Consequently, knowledge about involvement in interaction, egress additional replicative steps led postulation an antiviral target. Indeed, validation experiments vitro vivo confirmed sustainability this approach. current investigations treatment go beyond known ganciclovir prodrug activation henceforward include pUL97-specific inhibitors. Among number interesting small molecules analyzed preclinical stages, maribavir is presently investigated clinical studies and, near future, might represent first inhibitor applied field therapy.

Language: Английский

---

Viral-Host Dependency Factors as Therapeutic Targets to Overcome Antiviral Drug-Resistance: A Focus on Innate Immune Modulation

Frontiers in Virology, Journal Year: 2022, Volume and Issue: 2

Published: July 5, 2022

The development of antiviral drugs, has provided enormous achievements in our recent history the fight against viral infections. To date, most approved drugs target virus-encoded proteins to achieve direct activity. Nonetheless, inherent idiosyncrasy mutations during their replication cycle, enable many viruses adapt new barriers, becoming resistant therapies, therefore, representing an ever-present menace and prompting scientific community towards novel therapeutic strategies. Taking advantage increasing knowledge virus-host cell interactions, targeting cellular factors or pathways essential for virus survival turns into alternative strategy intervene almost every step cycle. Since host are evolutionary conserved, evasion host-directed therapies (HDT) would impose a higher genetic barrier emergence strains. Thus, long been considered overcome resistance. Nevertheless, potentially hints undesired off targets effects, critical risk-benefit evaluation is required. present review discusses current state-of-the-art on identification dependency (HDF) workflow required HDT as antivirals. Then, we focus feasibility using specific class factors, those involved innate immune modulation, broad-spectrum Finally, brief summary major roadblocks derived from putative future strategies its limitations proposed.

Language: Английский

---

Retroviral Restriction Factors and Their Viral Targets: Restriction Strategies and Evolutionary Adaptations

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

---

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

---

Schlafens Can Put Viruses to Sleep

Viruses, Journal Year: 2022, Volume and Issue: 14(2), P. 442 - 442

Published: Feb. 21, 2022

The Schlafen gene family encodes for proteins involved in various biological tasks, including cell proliferation, differentiation, and T development. Schlafens were initially discovered mice, have been studied the context of cancer biology, as well their role protecting cells during viral infection. This protein provides antiviral barriers via direct indirect effects on virus can inhibit replication viruses with both RNA DNA genomes. In this review, we summarize cellular functions emerging relationship between innate immunity. We also discuss distinctions host restriction factors against Further research into function will provide insight mechanisms that contribute to intrinsic

Language: Английский

---

SAMHD1 enhances HIV-1-induced apoptosis in monocytic cells via the mitochondrial pathway

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 10, 2025

SUMMARY Sterile alpha motif (SAM) and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) inhibits HIV-1 replication in non-dividing cells by reducing the intracellular dNTP pool. SAMHD1 enhances spontaneous apoptosis cells, but its effects on HIV-1-induced underlying mechanisms remain unknown. Here we uncover a new mechanism which monocytic through mitochondrial pathway. We found that endogenous levels induced infection dividing THP-1 cells. Mechanistically, expression decreases membrane potential promotes cytochrome c release thereby enhancing apoptotic SAMHD1-enhanced is associated with increased of pro-apoptotic BCL-2-interacting killer (BIK) further demonstrated BIK contributes to during infection. Overall, our results reveal an unappreciated regulatory via pathway

Language: Английский

---