Restriction Factors: From Intrinsic Viral Restriction to Shaping Cellular Immunity Against HIV-1

Frontiers in Immunology, Journal Year: 2018, Volume and Issue: 9

Published: Dec. 6, 2018

Antiviral restriction factors are host cellular proteins that constitute a first line of defense blocking viral replication and propagation. In addition to interfering at critical steps the cycle, some also act as innate sensors triggering responses against infections. Accumulating evidence suggests an additional role for in promoting antiviral immunity combat viruses. Here, we review recent progress our understanding on how factors, particularly APOBEC3G, SAMHD1, Tetherin, TRIM5α have cell-autonomous potential induce resistance HIV-1 while adaptive immune responses. Also, provide overview these may connect with protein degradation pathways modulate anti-HIV-1 responses, summarize factors-based therapeutics. This brings global perspective influence restrictions intrinsic, innate, opening up novel research avenues therapeutic strategies fields drug discovery, gene therapy, vaccines control

Language: Английский

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From APOBEC to ZAP: Diverse mechanisms used by cellular restriction factors to inhibit virus infections

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Journal Year: 2018, Volume and Issue: 1866(3), P. 382 - 394

Published: Oct. 2, 2018

Language: Английский

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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

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N6-methyladenosine modification of HIV-1 RNA suppresses type-I interferon induction in differentiated monocytic cells and primary macrophages

PLoS Pathogens, Journal Year: 2021, Volume and Issue: 17(3), P. e1009421 - e1009421

Published: March 10, 2021

N 6 -methyladenosine (m A) is a prevalent RNA modification that plays key role in regulating eukaryotic cellular mRNA functions. m A regulated by two groups of proteins, writers and erasers add or remove A, respectively. HIV-1 contains modifications modulate viral infection gene expression CD4 + T cells. However, it remains unclear whether innate immune responses myeloid cells are important for antiviral immunity. Here we show suppresses the cytokine type-I interferon (IFN-I) differentiated human monocytic primary monocyte-derived macrophages. Transfection U937 with fragments containing single A-modification significantly reduced IFN-I relative to their unmodified counterparts. We generated altered levels manipulating (FTO ALKBH5) pharmacological inhibition addition virus-producing cells, treating recombinant FTO vitro . transfection macrophages demonstrated decreased enhanced expression, whereas increased had opposite effects. Our mechanistic studies indicated escaped retinoic acid-induced I (RIG-I)-mediated sensing activation transcription factors IRF3 IRF7 drive expression. Together, these findings suggest evade

Language: Английский

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Antibiotic Chlortetracycline Causes Transgenerational Immunosuppression via NF-κB

Environmental Science & Technology, Journal Year: 2022, Volume and Issue: 56(7), P. 4251 - 4261

Published: March 14, 2022

The extensive and increasing global use of antibiotics results in the ubiquitous presence environment, which has made them "pseudo persistent organic contaminants." Despite numerous studies showing wide adverse effects on organisms, chronic environmental risk their exposure is unknown, molecular cellular mechanisms antibiotic toxicity remain unclear. Here, we systematically quantified transgenerational immune disturbances after parental to levels a common antibiotic, chlortetracycline (CTC), using zebrafish as model. CTC strongly reduced antibacterial activities fish offspring by immunosuppression. Both innate adaptive immunities were suppressed, significant perturbation macrophages neutrophils, expression immune-related genes, other functions. Moreover, these CTC-induced either prevented or alleviated supplementation with PDTC, an antagonist nuclear factor-κB (NF-κB), uncovering seminal role NF-κB immunotoxicity. Our provide evidence that at environmentally relevant concentrations can be transmitted over multiple generations weaken defense offspring, raising concerns population hazards ecological natural environment.

Language: Английский

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Single-cell analysis reveals altered tumor microenvironments of relapse- and remission-associated pediatric acute myeloid leukemia

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Oct. 5, 2023

Acute myeloid leukemia (AML) microenvironment exhibits cellular and molecular differences among various subtypes. Here, we utilize single-cell RNA sequencing (scRNA-seq) to analyze pediatric AML bone marrow (BM) samples from diagnosis (Dx), end of induction (EOI), relapse timepoints. Analysis Dx, EOI scRNA-seq, TARGET RNA-seq datasets reveals an blasts-associated 7-gene signature (CLEC11A, PRAME, AZU1, NREP, ARMH1, C1QBP, TRH), which validate on independent datasets. The analysis distinct clusters Dx relapse- continuous complete remission (CCR)-associated AML-blasts with differential expression genes associated survival. At relapse-associated have more exhausted T cells while CCR-associated inflammatory M1 macrophages. Post-therapy residual blasts overexpress fatty acid oxidation, tumor growth, stemness genes. Also, a post-therapy T-cell cluster downregulation MHC Class I regulatory Altogether, this study deeply characterizes provide insights into the BM landscape.

Language: Английский

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Hantaan virus glycoprotein Gc induces NEDD4‐dependent PTEN ubiquitination and degradation to escape the restriction of autophagosomes and facilitate viral propagation

The FASEB Journal, Journal Year: 2025, Volume and Issue: 39(1)

Published: Jan. 10, 2025

Abstract Hantaan virus (HTNV) infection causes severe hemorrhagic fever with renal syndrome (HFRS) in humans and the infectious process can be regulated by autophagy. The phosphatase tensin homolog (PTEN) protein has antiviral effects plays a critical role autophagy pathway. However, relationship between PTEN HTNV is not clear whether PTEN‐regulated involves replication unknown. Here, we identified that inhibits expression vitro vivo. glycoprotein Gc promotes ubiquitination degradation through 26S‐proteasome pathway via E3 ubiquitin ligase NEDD4. In addition, knockdown of prevents increases production, while overexpression induces autophagosome formation which wrap particles, thus leading to restrain production progeny viruses. Altogether, our findings reveal autophagy, highlighting potential importance treatment HFRS diseases.

Language: Английский

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Sensor Sensibility—HIV-1 and the Innate Immune Response

Cells, Journal Year: 2020, Volume and Issue: 9(1), P. 254 - 254

Published: Jan. 20, 2020

Innate immunity represents the human immune system's first line of defense against a pathogenic intruder and is initiated by recognition conserved molecular structures known as pathogen-associated patterns (PAMPs) specialized cellular sensors, called pattern receptors (PRRs). Human immunodeficiency virus type 1 (HIV-1) unique RNA that causes acquired syndrome (AIDS) in infected individuals. During replication cycle, HIV-1 undergoes reverse transcription its genome integrates resulting DNA into genome. Subsequently, integrated provirus results production new virions spreading infection virus. Throughout viral numerous nucleic acid derived PAMPs can be recognized diverse set innate sensors cells. However, has evolved efficient strategies to evade or counteract this surveillance downstream responses. Understanding underpinnings concerted actions system, well corresponding evasion mechanisms during infection, critical understanding transmission pathogenesis, may provide important guidance for design appropriate adjuvant vaccine strategies. Here, we summarize current knowledge basis sensing cells, including CD4+ T dendritic macrophages. Furthermore, discuss underlying which regulated, describe developed

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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TRIM21‐mediated proteasomal degradation of SAMHD1 regulates its antiviral activity

EMBO Reports, Journal Year: 2019, Volume and Issue: 21(1)

Published: Dec. 4, 2019

Abstract SAMHD 1 possesses multiple functions, but whether cellular factors regulate expression or its function remains not well characterized. Here, by investigating why cultured RD and HEK 293T cells show different sensitivity to enterovirus 71 (EV71) infection, we demonstrate that is a restriction factor for EV71. Importantly, identify TRIM 21, an E3 ubiquitin ligase, as key regulator of 1, which specifically interacts degrades through the proteasomal pathway. However, 21 has no effect on EV71 replication itself. Moreover, prove interferon production stimulated infection induces increased expression, whereas increasing overrides inhibition in neonatal mouse model. 21‐mediated degradation also affects 1‐dependent HIV ‐1 regulation production. We further functional domains required binding ubiquitination site K622 phosphorylation at T592 blocks restriction. Our findings illuminate how overcomes via upregulation 21.

Language: Английский

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