Intracellular Nucleic Acid Detection in Autoimmunity

Annual Review of Immunology, Journal Year: 2017, Volume and Issue: 35(1), P. 313 - 336

Published: March 30, 2017

Protective immune responses to viral infection are initiated by innate sensors that survey extracellular and intracellular space for foreign nucleic acids. The existence of these raises fundamental questions about self/nonself discrimination because the abundance self-DNA self-RNA occupy same compartments. Recent advances have revealed enzymes metabolize or modify endogenous acids essential preventing inappropriate activation antiviral response. In this review, we discuss rare human diseases caused dysregulated acid sensing, focusing primarily on We summarize lessons learned from disorders, rationalize in context evolution, propose framework may also apply a number more common autoimmune which underlying genetics mechanisms not yet fully understood.

Language: Английский

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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 suppresses innate immune responses to viral infections and inflammatory stimuli by inhibiting the NF-κB and interferon pathways

Proceedings of the National Academy of Sciences, Journal Year: 2018, Volume and Issue: 115(16)

Published: April 2, 2018

Sterile alpha motif and HD-domain-containing protein 1 (SAMHD1) blocks replication of retroviruses certain DNA viruses by reducing the intracellular dNTP pool. SAMHD1 has been suggested to down-regulate IFN inflammatory responses viral infections, although functions mechanisms in modulating innate immunity remain unclear. Here, we show that suppresses immune infections stimuli inhibiting nuclear factor-κB (NF-κB) activation type I interferon (IFN-I) induction. Compared with control cells, infection SAMHD1-silenced human monocytic cells or primary macrophages Sendai virus (SeV) HIV-1, treatment stimuli, induces significantly higher levels NF-κB IFN-I Exogenous expression reconstitution knockout induction SeV stimuli. Mechanistically, inhibits interacting NF-κB1/2 phosphorylation inhibitory IκBα. also interacts inhibitor-κB kinase ε (IKKε) regulatory factor 7 (IRF7), leading suppression pathway IKKε-mediated IRF7 phosphorylation. Interactions endogenous proteins were validated macrophages. Comparing splenocytes from heterozygous mice, further confirmed SAMHD1-mediated activation, suggesting an evolutionarily conserved property SAMHD1. Our findings reveal down-regulating highlighting importance antiviral immunity.

Language: Английский

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DMSO cryopreservation is the method of choice to preserve cells for droplet-based single-cell RNA sequencing

Scientific Reports, Journal Year: 2019, Volume and Issue: 9(1)

Published: July 23, 2019

Abstract Combining single-cell RNA sequencing (scRNA-seq) with upstream cell preservation procedures such as cryopreservation or methanol fixation has recently become more common. By separating handling and preparation, from downstream library generation, scRNA-seq workflows are flexible manageable. However, the inherent transcriptomic changes associated how they may bias further analysis remain unknown. Here, we present a side-by-side droplet-based analysis, comparing gold standard – fresh cells to three different workflows: dimethyl sulfoxide based cryopreservation, CellCover reagent. Cryopreservation proved be most robust protocol, maximizing both integrity low background ambient RNA. Importantly, gene expression profiles correlated those of cryopreserved cells. Such similarities were consistently observed across tested lines (R ≥ 0.97), monocyte-derived macrophages = 0.97) immune 0.99). In contrast, showed an increased overall lower correlation Thus, our results demonstrate superiority over other methods. We expect comparative study provide omics researchers invaluable support when integrating into their studies.

Language: Английский

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SAMHD1 controls cell cycle status, apoptosis and HIV-1 infection in monocytic THP-1 cells

Virology, Journal Year: 2016, Volume and Issue: 495, P. 92 - 100

Published: May 13, 2016

Language: Английский

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SAMHD1-mediated HIV-1 restriction in cells does not involve ribonuclease activity

Nature Medicine, Journal Year: 2016, Volume and Issue: 22(10), P. 1072 - 1074

Published: Oct. 1, 2016

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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SAMHD1: At the Crossroads of Cell Proliferation, Immune Responses, and Virus Restriction

Trends in Microbiology, Journal Year: 2015, Volume and Issue: 23(11), P. 680 - 692

Published: Oct. 3, 2015

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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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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