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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SAMHD1 Promotes DNA End Resection to Facilitate DNA Repair by Homologous Recombination

Cell Reports, Journal Year: 2017, Volume and Issue: 20(8), P. 1921 - 1935

Published: Aug. 1, 2017

Highlights•SAMHD1 deficiency or Vpx-mediated degradation sensitizes cells to DSB-inducing agents•SAMHD1 localizes DNA double-strand breaks in response damage•SAMHD1 promotes HR and end resection independent of its dNTPase activity•SAMHD1 complexes with CtIP facilitates recruitment damage sitesSummaryDNA break (DSB) repair by homologous recombination (HR) is initiated CtIP/MRN-mediated maintain genome integrity. SAMHD1 a dNTP triphosphohydrolase, which restricts HIV-1 infection, mutations are associated Aicardi-Goutières syndrome cancer. We show that has dNTPase-independent function promoting facilitate DSB HR. causes hypersensitivity agents, recruited DSBs. via conserved C-terminal domain recruits DSBs Significantly, cancer-associated mutant impaired interaction, but not dNTPase-inactive SAMHD1, fails rescue the impairment depletion. Our findings define for HR-mediated facilitating accrual promote resection, providing insight into how integrity.Graphical abstract

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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N6-Methyladenosine–binding proteins suppress HIV-1 infectivity and viral production

Journal of Biological Chemistry, Journal Year: 2018, Volume and Issue: 293(34), P. 12992 - 13005

Published: July 5, 2018

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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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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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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