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

---

Harnessing miRNA Dynamics in HIV-1-Infected Macrophages: Unveiling New Targeted Therapeutics using Systems Biology

Computational and Structural Biotechnology Journal, Journal Year: 2025, Volume and Issue: unknown

Published: May 1, 2025

Language: Английский

---

Host Restriction Factors Modulating HIV Latency and Replication in Macrophages

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(6), P. 3021 - 3021

Published: March 11, 2022

In addition to CD4+ T lymphocytes, myeloid cells and, particularly, differentiated macrophages are targets of human immunodeficiency virus type-1 (HIV-1) infection via the interaction gp120Env with CD4 and CCR5 or CXCR4. Both support replication, although substantial differences. contrast activated HIV-1 replication in occurs nondividing it is characterized by virtual absence cytopathicity both vitro vivo. These general features should be considered evaluating role cell-associated restriction factors aiming at preventing curtailing cells, particularly context designing strategies tackle viral reservoir infected individuals receiving combination antiretroviral therapy. this regard, we will here also discuss a model reversible latency primary host determining reactivation these cells.

Language: Английский

---

Immunomodulatory Effects of Symplectoteuthis oualaniensis Protamine and Its PEG Derivative on Macrophages: Involvement of PI3K/Akt Signaling, Redox Regulation, and Cell Cycle Modulation

Antioxidants, Journal Year: 2025, Volume and Issue: 14(4), P. 437 - 437

Published: April 4, 2025

Protamine is a promising marine-derived bioactive compound that highly arginine-rich and has demonstrated unique advantages in medical biological research. This study, for the first time, investigates molecular mechanisms underlying immunomodulatory effects of Salmon Sulfate (SPS), Symplectoteuthis oualaniensis (SOP), its polyethylene glycol (PEG) derivative (SOP-PEG) on RAW264.7 macrophages. The results demonstrate both SOP SOP-PEG significantly enhance proliferation cells by promoting secretion pro-inflammatory cytokines nitric oxide (NO), increasing ROS production, improving antioxidant capacity, comparison to SPS. Elevated levels play crucial role enhancing macrophage immune activity, while enhanced defense help maintain redox homeostasis protect against oxidative stress-induced cellular damage. A Western blot analysis reveals notably regulate expression key proteins associated with PI3K/Akt signaling pathway anti-apoptotic mechanisms. Furthermore, flow cytometry indicates significant increase G2/M-phase cell population treatment groups, which corroborated data showing alterations critical regulatory proteins. Notably, exhibits strongest regulating can be attributed stability prolonged bioactivity resulting from PEGylation SOP. comprehensive study how function through multiple mechanisms, including activation, regulation, cycle modulation. It provides valuable insights theoretical foundation their potential applications immunotherapy regulation.

Language: Английский

---

The Role of MicroRNA in DNA Damage Response

Frontiers in Genetics, Journal Year: 2022, Volume and Issue: 13

Published: May 3, 2022

DNA is essential for the development and function of organisms. A number factors affect integrity cause damages, such as ultraviolet light, ionizing radiation hydrogen peroxide. damages activate a series intracellular reactions, called damage response, which play crucial role in pathogenesis cancers other diseases. MiRNA type evolutionarily conserved non-coding RNA affects expression target genes by post-transcriptional regulation. Increasing evidences suggested that some miRNAs was changed tumor cases. MiRNAs may participate response genomic stability via influencing processes cell cycle, repair apoptosis, thus ultimately impact on tumorigenesis. Therefore, miRNA reviewed, to provide theoretical basis mechanism miRNAs' effects research new therapies

Language: Английский

---

Hypoxia drives HIF2-dependent reversible macrophage cell cycle entry

Cell Reports, Journal Year: 2024, Volume and Issue: 43(7), P. 114471 - 114471

Published: July 1, 2024

Low-oxygen conditions (hypoxia) have been associated primarily with cell-cycle arrest in dividing cells. Macrophages are typically quiescent G0 but can proliferate response to tissue signals. Here we show that hypoxia (1% oxygen tension) results reversible entry into the cell cycle macrophages. Cell progression is largely limited G0-G1/S phase transition little G2/M. This transitioning triggered by an HIF2α-directed transcriptional program. The accompanied increased expression of cell-cycle-associated proteins, including CDK1, which known phosphorylate SAMHD1 at T592 and thereby regulate antiviral activity. Prolyl hydroxylase (PHD) inhibitors able recapitulate HIF2α-dependent Finally, tumor-associated macrophages (TAMs) lung cancers exhibit transcriptomic profiles representing responses low single-cell level. These findings implications for inflammation tumor progression/metastasis where low-oxygen environments common.

Language: Английский

---

Phosphorylation of SAMHD1 Thr592 increases C-terminal domain dynamics, tetramer dissociation and ssDNA binding kinetics

Nucleic Acids Research, Journal Year: 2022, Volume and Issue: 50(13), P. 7545 - 7559

Published: July 8, 2022

Abstract SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1) is driven into its activated tetramer form by binding of GTP activator dNTP activators/substrates. In addition, the inactive monomeric dimeric forms enzyme bind to single-stranded (ss) nucleic acids. During DNA replication SAMHD1 can be phosphorylated CDK1 CDK2 at C-terminal threonine 592 (pSAMHD1), localizing stalled forks (RFs) promote their restart. Although phosphorylation has only a small effect on dNTPase activity ssDNA affinity SAMHD1, perturbation native T592 decreased thermal stability tetrameric accelerated dissociation in absence presence (∼15-fold). we found that binds competitively with A1 site. A full-length cryo-EM structure revealed substantial dynamics (which contains T592), which could modulated phosphorylation. We propose increases allows invasion site previously characterized surface dimer-dimer interface. These features are consistent rapid regiospecific inactivation pSAMHD1 RFs or other sites free cells.

Language: Английский

---

iPS cell–derived model to study the interaction between tissue macrophage and HIV-1

Journal of Leukocyte Biology, Journal Year: 2023, Volume and Issue: 114(1), P. 53 - 67

Published: March 15, 2023

Abstract Despite effective antiretroviral therapy, HIV-1 persists in cells, including macrophages, which is an obstacle to cure. However, the precise role of macrophages infection remains unclear because they reside tissues that are not easily accessible. Monocyte-derived widely used as a model peripheral blood monocytes cultured and differentiated into macrophages. another needed recent studies revealed most adult originate from yolk sac fetal liver precursors rather than monocytes, embryonic possess self-renewal (proliferating) capacity monocyte-derived lack. Here, we show human induced pluripotent stem cell–derived immortalized macrophage-like cells useful self-renewing macrophage model. They proliferate cytokine-dependent manner, retain functions, support replication, exhibit infected macrophage–like phenotypes, such enhanced tunneling nanotube formation cell motility, well resistance viral cytopathic effect. several differences also observed between can be explained by proliferation cells. For instance, proviruses with large internal deletions, increased over time individuals receiving enriched more rapidly Interestingly, inhibition transcription HIV-1–suppressing agents obvious Collectively, our present study proposes suitable for mimicking interplay tissue newly recognized major population cannot fully modeled alone.

Language: Английский

---

Altered Host microRNAomics in HIV Infections: Therapeutic Potentials and Limitations

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(16), P. 8809 - 8809

Published: Aug. 13, 2024

microRNAs have emerged as essential regulators of health and disease, attracting significant attention from researchers across diverse disciplines. Following their identification noncoding oligonucleotides intricately involved in post-transcriptional regulation protein expression, extensive efforts were devoted to elucidating validating roles fundamental metabolic pathways multiple pathologies. Viral infections are modifiers the host microRNAome. Specifically, Human Immunodeficiency Virus (HIV), which affects approximately 39 million people worldwide has no definitive cure, was reported induce changes cell miRNA profiles. Identifying understanding effects aberrant microRNAome holds potential for early detection therapeutic designs. This review presents a comprehensive overview impact HIV on We aim cause-and-effect relationship between HIV-induced that underscores miRNA’s acknowledge its limitations.

Language: Английский

---

Pro-inflammatory macrophages suppress HIV replication in humanized mice and ex vivo co-cultures

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Nov. 7, 2024

Introduction Very little is known about the role of macrophages as immune mediators during natural HIV infection. Humanized mice are an extremely valuable in vivo model for studying pathogenesis. However, presence murine mononuclear phagocytes these models represents a significant limitation their human counterpart. Therefore, we have developed novel humanized mouse that allows selective depletion myeloid cells at time point our choosing. Methods We genetically engineered hematopoietic stem and progenitor (HSPCs) to express inducible caspase-9 (iCas9) suicide system under synthetic promoter. Using HSPCs, generated mice. iCasp9 induction resulted cell death this (iHMD) model. In addition, co-cultured monocyte-derived with ex HIV-infected PBMCs further mechanistically investigate effect on replication using flow cytometry, cytokine analysis, RNA sequencing both CD4+ T cells. Results infection induced pro-inflammatory phenotype NSG early late stages Myeloid iHMD-NSG rapid increase replication, which was accompanied by loss cytokines. Co-culture reproduced anti-HIV effects observed . Transcriptomic data showed upregulate antiviral cytokines chemokines co-culture, while inducing restriction factors downregulate pathways involved protein expression replication. Discussion This study describes effector cells, , acting against limiting disease progression.

Language: Английский

---