When DNA-damage responses meet innate and adaptive immunity

Cellular and Molecular Life Sciences, Journal Year: 2024, Volume and Issue: 81(1)

Published: April 17, 2024

Abstract When cells proliferate, stress on DNA replication or exposure to endogenous external insults frequently results in damage. DNA-Damage Response (DDR) networks are complex signaling pathways used by multicellular organisms prevent Depending the type of broken DNA, various pathways, Base-Excision Repair (BER), Nucleotide Excision (NER), Mismatch (MMR), Homologous Recombination (HR), Non-Homologous End-Joining (NHEJ), Interstrand Crosslink (ICL) repair, and other direct repair can be activated separately combination To preserve homeostasis, innate adaptive immune responses effective defenses against mutation invasion pathogens. It is interesting note that new research keeps showing how closely DDR components system related. immunological response linked effectors such as cyclic GMP-AMP synthase (cGAS)–Stimulator Interferon Genes (STING) pathway. These act sensors damage-caused response. Furthermore, themselves function trigger generation inflammatory cytokines a cascade even programmed cell death. Defective known disrupt genomic stability compromise responses, aggravating imbalance leading serious diseases cancer autoimmune disorders. This study examines most recent developments interaction between elements responses. The network’s modulators’ dual roles may offer perspectives treating infectious disorders damage, including cancer, development target immunotherapy.

Language: Английский

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IFN Regulatory Factor 3 in Health and Disease

The Journal of Immunology, Journal Year: 2020, Volume and Issue: 205(8), P. 1981 - 1989

Published: Oct. 6, 2020

Immunity to viruses requires an array of critical cellular proteins that include IFN regulatory factor 3 (IRF3). Consequently, most infect vertebrates encode interfere with IRF3 activation. This review describes the pathways linked activation and where those are targeted by human viral pathogens. Moreover, key control discussed. Besides infections, is also involved in resistance some bacterial anticancer immunity, therapies involving DNA damage agents. A recent finding shows needed for T cell effector functions immunity autoimmune diseases. In contrast, unregulated activity clearly not beneficial, considering it implicated certain interferonopathies, which heightened leads IFN-β-induced disease. Therefore, largely maintaining health but sometimes contributing

Language: Английский

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SAMHD1 Modulates Early Steps during Human Cytomegalovirus Infection by Limiting NF-κB Activation

Cell Reports, Journal Year: 2019, Volume and Issue: 28(2), P. 434 - 448.e6

Published: July 1, 2019

Highlights•HCMV infection induces SAMHD1 expression and phosphorylation•SAMHD1 restricts HCMV gene before virus replication•SAMHD1 deficiency limits entry into the quiescent stage of infection•HCMV restriction by is mediated limiting NF-κB activationSummaryCellular inhibits replication many viruses intracellular deoxynucleoside triphosphate (dNTP) pools. We investigate influence on human cytomegalovirus (HCMV). During infection, we observe induction, accompanied phosphorylation via viral kinase UL97. depletion increases in permissive fibroblasts conditionally myeloid cells. show this due to enhanced from major immediate-early (MIE) promoter independent dNTP levels. suppresses innate immune responses inhibiting nuclear factor κB (NF-κB) activation. that regulates MIE through Chromatin immunoprecipitation reveals increased RELA RNA polymerase II absence SAMHD1. Our studies reveal a mechanism how activates an pathway paradoxically results transcriptional activation promoter.Graphical abstract

Language: Английский

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The regulatory landscape of macrophage interferon signaling in inflammation

Journal of Allergy and Clinical Immunology, Journal Year: 2023, Volume and Issue: 152(2), P. 326 - 337

Published: June 3, 2023

The pervasive role of the innate immune system is established by interferons. Emerging research shows an underappreciated ability macrophages to regulate and propagate interferon responses in infectious autoinflammatory disease states. In this review, we will discuss recent findings demonstrating immunomodulating effects macrophage signaling. Apart from provoking cellular antimicrobial defenses, interferons augment inflammatory activity macrophages. These immunologic adaptations place center at forefront immunity. Consequently, are implicated pathogenesis interferon-driven disorders, such as SLE. these states, recognition immunogenic ligands triggers adopt phenotype through This amplify responses, eventually leading autoinflammation. A better understanding macrophage's signaling support future elucidation novel targets amendable for clinical treatment. Interferons (IFNs) underlie competence ward off pathogens. viral infections, IFNs secreted induce antiviral state host cells, supporting our first line defense against pathogens.1Durbin J.E. Fernandez-Sesma A. Lee C.K. Rao T.D. Frey A.B. Moran T.M. et al.Type I IFN modulates specific immunity.J Immunol. 2000; 164: 4220-4228Crossref PubMed Google Scholar Moreover, recruit leukocytes site infection their activity.2Lee A.J. Ashkar A.A. dual nature type II interferons.Front 2018; 9: 2061Crossref Scopus (343) measures ultimately aim interfere with replication dissemination, curtailing infection. Perturbed may therefore severity susceptibility infections.3Posseme C. Llibre Charbit B. Bondet V. Rouilly Saint-André al.Early IFNβ secretion determines variable downstream IL-12p70 upon TLR4 activation.Cell Rep. 2022; 39110989Abstract Full Text PDF (0) Predictably, impaired a hallmark severe COVID-19 manifestation.4Stertz S. Hale B.G. Interferon deficiencies exacerbating pandemic virus infections.Trends Microbiol. 2021; 29: 973-982Abstract Scholar,5Hadjadj J. Yatim N. Barnabei L. Corneau Boussier Smith al.Impaired patients.Science (1979). 2020; 369: 718-724Crossref More than half century since discovery, now known extend well beyond responses. Namely, orchestrate various distinct homeostatic processes maintain physiological integrity.6Place D.E. Malireddi R.K.S. Kim Vogel P. Yamamoto M. Kanneganti Osteoclast fusion bone loss restricted inducible guanylate binding proteins.Nat Commun. 12: 1-9Crossref (35) Scholar,7Katlinskaya Y.V. Katlinski K.V. Lasri Li Beiting D.P. Durham A.C. control proliferation function intestinal epithelium.Mol Cell Biol. 2016; 36: 1124-1135Crossref (26) Accordingly, disconcerted have long been drive SLE Aicardi-Goutières syndrome. addition, commonly contribute local or systemic inflammation seen rheumatoid arthritis activation Because perturbed appears common denominator conditions, they widely recognized so-called interferonopathies. necessitates investigative efforts into all facets infer clinically relevant reduce burden disease. directed toward interfering microbial principally enhancing interferon-stimulated gene (ISG) expression. On infection, nearly any cell produce intrinsic response microbials, but also protect neighboring cells activate leukocytes. Purposely, some competent producers themselves highly responsive regulatory IFNs, forming feed-forward loop. capacity dependent on lineage microenvironment, like presence pathogens cytokines. Classically, there lineages specialized types IFNs. 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Priming: nonantiviral interferon.J Virol. 1971; 7: 792Crossref Since then, comprise 3 classes cytokines: I, There several subclasses (including IFN-α subtypes IFN-β) (IFN-λ1 4), single (IFN-γ). evolutionary advantage largely unknown, functional differences come down receptor affinity.20Wittling M.C. Cahalan S.R. Levenson E.A. Rabin R.L. Shared unique features interferon-beta interferon-alpha subtypes.Front 3325Crossref (22) Scholar,21Jaks Gavutis Uzé Martal Piehler Differential subunit affinities govern differential signal activation.J 366: 525-539Crossref (166) Despite shared nomenclature, different share little structural homology.22Ealick S.E. Cook W.J. Vijay-Kumar Carson Nagabhushan T.L. Trotta P.P. al.Three-dimensional structure recombinant interferon-γ.Science 1991; 252: 698-702Crossref 23Radhakrishnan Walter L.J. Hruza Reichert al.Zinc mediated dimer 2b revealed X-ray crystallography.Structure. 1996; 4: 1453-1463Abstract 24Karpusas Nolte Benton Meier W. Lipscomb W.N. Goelz crystal beta 2.2-A resolution.Proc Natl Acad Sci U S 1997; 94: 11813-11818Crossref each class binds receptor, canonically eliciting Their commonality role, exerting either autocrine paracrine (Fig 1). Biochemically, IFN-α/β 2 conformational change, allowing tyrosine kinase Janus (JAK) phosphorylate transducer activator transcription (STAT1) (STAT2), causing heterodimerization. STAT1/STAT2 recruits factor 9 (IRF9) assemble heterotrimeric complex IFN-stimulated (ISGF3). Distinctly, IFN-γ 2, JAK1- JAK2-mediated phosphorylation homodimerization STAT1. newly formed translocate nucleus bind gamma-activated sequence promoter elements, ISGF3 elements (ISREs), promoting expression ISGs. Type heterodimeric IFN-λ IL-10 subunit, pathway ISGs located ISREs, mainly encoding proteins properties pathogenic exposures. Some most well-characterized oligoadenylate synthetases, IFN-induced tetratricopeptide repeats, GTP-binding protein. 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Language: Английский

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Nucleic acid binding by SAMHD1 contributes to the antiretroviral activity and is enhanced by the GpsN modification

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

Published: Feb. 2, 2021

Abstract SAMHD1 impedes infection of myeloid cells and resting T lymphocytes by retroviruses, the enzymatic activity protein—dephosphorylation deoxynucleotide triphosphates (dNTPs)—implicates dNTP depletion in innate antiviral immunity. Here we show that allosteric binding sites enzyme are plastic can accommodate oligonucleotides place activators, GTP dNTP. displays a preference for containing phosphorothioate bonds Rp configuration located 3’ to G nucleotides (GpsN), modification pattern occurs mechanism defense prokaryotes. In presence dNTPs, GpsN-containing promotes formation distinct tetramer with mixed occupancy sites. Mutations impair mixed-occupancy complex abolish antiretroviral SAMHD1, but not its ability deplete dNTPs. The findings link nucleic acid shed light on immunomodulatory effects synthetic phosphorothioated raise questions about role phosphorothioation human

Language: Английский

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Glycosylated diphyllin as a broad-spectrum antiviral agent against Zika virus

EBioMedicine, Journal Year: 2019, Volume and Issue: 47, P. 269 - 283

Published: Sept. 1, 2019

BackgroundFlaviviruses such as Zika cause sporadic pandemic outbreaks worldwide. There is an urgent need for anti-Zika virus (ZIKV) drugs to prevent mother-to-child transmission of ZIKV, new infections in high-risk populations, and the infection medical personnel ZIKV-affected areas.MethodsHere, we showed that small molecule 6-deoxyglucose-diphyllin (DGP) exhibited anti-ZIKV activity both vitro vivo. DGP potently blocked ZIKV across all human monkey cell lines tested. also displayed broad-spectrum antiviral against other flaviviruses. Remarkably, prevented ZIKV-induced mortality mice lacking type I interferon receptor (Ifnar1−/−). Cellular virological experiments at a pre-fusion step or during fusion, which delivery viral contents into cytosol target cell. Mechanistic studies revealed acidification endosomal/lysosomal compartments cells, thus inhibiting fusion with cellular membranes infection.FindingsThese investigations inhibits vivo.InterpretationThe has great potential preclinical ability inhibit humans.

Language: Английский

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SAMHD1 dysfunction induces IL-34 expression via NF-κB p65 in neuronal SH-SY5Y cells

Molecular Immunology, Journal Year: 2024, Volume and Issue: 168, P. 1 - 9

Published: Feb. 17, 2024

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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Increased interferon I signaling, DNA damage response and evidence of T-cell exhaustion in a patient with combined interferonopathy (Aicardi-Goutières Syndrome, AGS) and cohesinopathy (Cornelia de Lange Syndrome, CdLS)

Pediatric Rheumatology, Journal Year: 2025, Volume and Issue: 23(1)

Published: Jan. 27, 2025

Abstract Background Type I interferonopathies including Aicardi-Goutiéres Syndrome (AGS) represent a heterogeneous group of clinical phenotypes. Herein, we present Case with combined AGS and Cornelia de Lange (CdLS)—a cohesinopathy—with comprehensive analysis the immune genomic abnormalities. methods A 20-year old man presented chilblain lesions resorption distal phalanges fingers toes, somatic psychomotor retardation, microcephaly, synophrys, hearing losing other aberrancies consistent phenotype CdLS. We used whole exome sequencing to genetically map associated mutations performed transcriptome profiling enrichment in CD14 + monocytes patient phenotyping by mass cytometry (CyToF), comparing healthy individuals lupus patients as disease controls. DNA damage response was assayed confocal microscopy peripheral blood this patient. Results Next generation confirmed homozygous SAMHD1 gene mutation hemizygous non-synonymous on SMC1A gene, responsible for CdLS, respectively. Transcriptome showed type IFN signaling enhanced pathway. Broad revealed absence activated T cell populations, increased frequency NK cells plasmablasts granulocytic lineage. Further suggested activation ATM branch apoptosis periphery Conclusions rare case bearing two genetic (responsible AGS/CdLS syndromes) exhibits distinctive features interferon responses. Immune skewing compatible chronic antigenic stimulation and/or homing these at sites inflammation.

Language: Английский

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SAMHD1 deficiency enhances macrophage-mediated clearance of Salmonella Typhimurium via NF-κB activation in zebrafish

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: April 25, 2025

Mutations in the gene encoding protein containing sterile alpha motif and HD domain (SAMHD1) have been implicated occurrence of type I interferonopathies. SAMHD1 is also involved blocking replication retroviruses certain DNA viruses by reducing intracellular amount deoxynucleotide triphosphates (dNTPs). It has suggested that negatively regulates interferon (IFN) inflammatory responses to viral infections; however, functions mechanisms modulating innate immunity are still under study. In our laboratory, we generated Samhd1-deficient zebrafish larvae using CRISPR-Cas9 studied its role activation nuclear factor kappa B (NF-κB) induction IFN (IFN-I). was shown Samhd1 deficiency results overactivation IFN-I response, assayed as increased transcript levels Interferon Stimulated Genes (ISGs), but only if were stimulated with suboptimal doses IFN-I. However, showed robust spontaneous NF-κB, which led larval resistance Salmonella enterica serovar Typhimurium (STM) infection. Genetic experiments further NF-κB macrophages mediated against STM. These findings highlight evolutionary conserved negative regulation response vertebrates reveal, for first time, a critical clear bacterial

Language: Английский

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