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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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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MicroRNA Mimics or Inhibitors as Antiviral Therapeutic Approaches Against COVID-19

Drugs, Journal Year: 2021, Volume and Issue: 81(5), P. 517 - 531

Published: Feb. 27, 2021

Coronaviruses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for the disease 2019 (COVID-19) pandemic, present a significant threat to human health by inflicting wide variety of complications and even death. While conventional therapeutics often involve administering small molecules fight viral infections, non-coding RNA sequences, known microRNAs (miRNAs/miR-), may novel antiviral strategy. We can take advantage their ability modulate host-virus interactions through mediating degradation or translational inhibition. Investigations into miRNA SARS-CoV-2 reveal therapeutic approaches against this virus. The genomes SARS-CoV-2, (SARS-CoV), Middle East (MERS-CoV) were searched using Nucleotide Basic Local Alignment Search Tool (BLASTn) highly similar identify potential binding sites miRNAs hypothesized play role in infection. that target angiotensin-converting enzyme (ACE2), receptor used SARS-CoV host cell entry, also predicted. Several relevant identified, roles regulating infections further assessed. Current treatment options are limited have not generated sufficient evidence on safety efficacy treating COVID-19. Therefore, investigating between miRNA-based therapies, including mimics inhibitors, be developed an alternative strategy

Language: Английский

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Interferons: Reprogramming the Metabolic Network against Viral Infection

Viruses, Journal Year: 2018, Volume and Issue: 10(1), P. 36 - 36

Published: Jan. 13, 2018

Viruses exploit the host and induce drastic metabolic changes to ensure an optimal environment for replication production of viral progenies. In response, has developed diverse countermeasures sense limit these alterations combat infection. One such mechanism is through interferon signaling. Interferons are cytokines that enhances transcription hundreds interferon-stimulated genes (ISGs) whose products key players in innate immune response addition their direct targeting components, interferons ISGs exert profound effects on cellular metabolism. Recent studies have started illuminate specific role rewiring metabolism activate cells This review reflects our current understanding complex networking occurs between virus at interface metabolism, with a focus particular, cholesterol-25-hydroxylase (CH25H), spermidine/spermine acetyltransferase 1 (SAT1), indoleamine-2,3-dioxygenase (IDO1) sterile alpha motif histidine/aspartic acid domain-containing protein (SAMHD1), which were recently discovered modulate events consequently deter

Language: Английский

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Immune signatures correlate with L1 retrotransposition in gastrointestinal cancers

Genome Research, Journal Year: 2018, Volume and Issue: 28(8), P. 1136 - 1146

Published: July 3, 2018

Long interspersed nuclear element-1 (LINE-1 or L1) retrotransposons are normally suppressed in somatic tissues mainly due to DNA methylation and antiviral defense. However, the mechanism suppress L1s may be disrupted cancers, thus allowing act as insertional mutagens cause genomic rearrangement instability. Whereas frequency of L1 insertions varies greatly among individual tumors, much remains learned about underlying genetic, cellular, environmental factors. Here, we report multiple correlates activity stomach, colorectal, esophageal tumors through an integrative analysis cancer whole-genome matched RNA-sequencing profiles. Clinical indicators tumor progression, such grade patient age, showed positive association. A potential expression suppressor, TP53, was mutated with frequent insertions. We characterized effects on mRNA splicing expression, demonstrated increased risk gene disruption retrotransposition-prone cancers. In particular, found that a cancer-specific insertion exon MOV10, key caused skipping decreased affected allele nonsense-mediated decay high load. Importantly, immune activity, for example, those associated Epstein-Barr virus infection microsatellite instability, tended carry low number genomes levels suppressors APOBEC3s SAMHD1 Our results indicate immunity contribute genome stability by suppressing retrotransposition gastrointestinal

Language: Английский

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SAMHD1 Suppression of Antiviral Immune Responses

Trends in Microbiology, Journal Year: 2018, Volume and Issue: 27(3), P. 254 - 267

Published: Oct. 15, 2018

Language: Английский

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ISG15 Connects Autophagy and IFN-γ-Dependent Control of Toxoplasma gondii Infection in Human Cells

mBio, Journal Year: 2020, Volume and Issue: 11(5)

Published: Oct. 5, 2020

Interferon(s) provide the primary defense against intracellular pathogens, a property ascribed to their ability upregulate interferon-stimulated genes. Due sequestered niche occupied by Toxoplasma gondii , host has elaborated intricate ways target parasite within its vacuole. One such mechanism is recognition noncanonical autophagy pathway that envelops parasite-containing vacuole and stunts growth in human cells. Remarkably, autophagy-dependent restriction requires interferon-γ, yet none of classical components are induced interferon. Our studies draw connection between these pathways demonstrating antiviral protein ISG15, which normally upregulated interferons, links autophagy-mediated control ubiquitination These findings suggest similar link interferon-γ signaling may underlie other pathogens.

Language: Английский

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Human cytomegalovirus overcomes SAMHD1 restriction in macrophages via pUL97

Nature Microbiology, Journal Year: 2019, Volume and Issue: 4(12), P. 2260 - 2272

Published: Sept. 23, 2019

Language: Английский

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SAMHD1: Recurring roles in cell cycle, viral restriction, cancer, and innate immunity

Autoimmunity, Journal Year: 2018, Volume and Issue: 51(3), P. 96 - 110

Published: March 27, 2018

Sterile alpha motif and histidine-aspartic acid domain-containing protein 1 (SAMHD1) is a deoxynucleotide triphosphate (dNTP) hydrolase that plays an important role in the homeostatic balance of cellular dNTPs. Its emerging as effector innate immunity affirmed by mutations SAMHD1 gene cause severe autoimmune disease, Aicardi–Goutieres syndrome (AGS) are linked to cancer. Additionally, functions restriction factor for retroviruses, such HIV. Here, we review current biochemical biological properties enzyme including its structure, activity, regulation post-translational modifications context function. We outline open questions regarding biology whose answers will be understanding function regulator cell cycle progression, genomic integrity, autoimmunity.

Language: Английский

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Impaired influenza A virus replication by the host restriction factor SAMHD1 which inhibited by PA-mediated dephosphorylation of the host transcription factor IRF3

Virology Journal, Journal Year: 2024, Volume and Issue: 21(1)

Published: Jan. 29, 2024

Abstract Background Influenza A virus (IAV) can cause severe and life-threatening illness in humans animals. Therefore, it is important to search for host antiviral proteins elucidate their mechanisms the development of potential treatments. As a part human innate immunity, restriction factors inhibit replication viruses, among which SAM HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1) restrict such as HIV enterovirus EV71. Viruses also developed countermeasures arms race with hosts. There are few reports about whether SAMHD1 has effect on IAV. Methods To investigate impact IAV infection expression A549 cells, we infected cells varying multiplicity (MOI) collected cell samples at different time points WB RT-qPCR analysis detect viral protein levels. The level culture supernatant was determined using TCID50 assay. Luciferase assay used reveal that H5N1 polymerase acidic (PA) affected activity promoter. assess capacity SAMHD1, generated knockdown overexpressed line detecting replication. Results In this study, observed intracellular PA downregulate by affecting transcriptional promoter activity. We found SAMHD1's ability related phosphorylation 592-tyrosine. Conclusions conclusion, may affect IAVs factor be countered PA. Furthermore, target developing drugs.

Language: Английский

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