An isoform of Dicer protects mammalian stem cells against multiple RNA viruses
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA727586 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14435492.fastq.gz | Fastqsanger.gz | |||
| SRR14435493.fastq.gz | Fastqsanger.gz | |||
| SRR14435494.fastq.gz | Fastqsanger.gz | |||
| SRR14435495.fastq.gz | Fastqsanger.gz | |||
| SRR14435496.fastq.gz | Fastqsanger.gz |
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Project description:In mammals, early resistance to viruses relies on interferons, which protect differentiated but not stem cells from viral replication. Many other organisms rely instead on RNA interference (RNAi) mediated by a specialised Dicer protein that cleaves viral double stranded RNA. Whether RNAi also contributes to mammalian antiviral immunity remains controversial. Here we identify an isoform of Dicer, named antiviral Dicer (aviD), that protects tissue stem cells from RNA viruses, including Zika virus and SARS-CoV-2, by dicing viral double-stranded RNA to orchestrate antiviral RNAi. Our work sheds light on the molecular regulation of antiviral RNAi in mammalian innate immunity in which different cell-intrinsic antiviral pathways are tailored to the differentiation status of cells.
2021-07-09 | GSE173946 | GEO
Project description:In mammals, early resistance to viruses relies on interferons, which protect differentiated cells but not stem cells from viral replication. Many other organisms rely instead on RNA interference (RNAi) mediated by a specialized Dicer protein that cleaves viral double-stranded RNA. Whether RNAi also contributes to mammalian antiviral immunity remains controversial. We identified an isoform of Dicer, named antiviral Dicer (aviD), that protects tissue stem cells from RNA viruses-including Zika virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-by dicing viral double-stranded RNA to orchestrate antiviral RNAi. Our work sheds light on the molecular regulation of antiviral RNAi in mammalian innate immunity, in which different cell-intrinsic antiviral pathways can be tailored to the differentiation status of cells.
| S-EPMC7611482 | biostudies-literature
Project description:The innate immune response against viruses mainly involves type I interferon (IFN) in mammalian cells. The exact contribution of the RNA silencing machinery remains to be established, but several recent studies indicate that the type III ribonuclease DICER can generate viral siRNAs in specific conditions. In addition, it has been proposed that type I IFN and RNA silencing could be mutually exclusive responses. In order to decipher the implication of DICER during infection of human cells with the Sindbis virus, we determined its interactome by immunoprecipitation and mass spectrometry analysis. Our results show that human DICER specifically interacts with several double-stranded RNA binding proteins and helicases during viral infection. In particular, proteins such as DHX9, ADAR-1 and the protein kinase PKR are enriched with DICER in virus-infected cells. We validated the importance of the helicase domain of DICER in its interaction with PKR and showed that it has functional consequences for the cellular response to viral infection.
2021-04-15 | PXD019093 | Pride
Project description:Drosophila Dicer-1 produces microRNAs (miRNAs) from pre-miRNA, whereas Dicer-2 generates small interfering RNAs (siRNAs) from long dsRNA. loquacious (loqs) encodes three Dicer partner proteins, Loqs-PA, Loqs-PB, and, Loqs-PD, generated by alternative splicing. To understand the function of each Loqs isoform, we constructed loqs isoform-specific rescue flies. Loqs-PD promotes siRNA production in vivo by Dicer-2. Loqs-PA or Loqs-PB is required for viability, but the proteins are not fully redundant: Loqs-PB is required to produce a specific subset of miRNAs. Surprisingly, Loqs-PB tunes the product size cleaved by Dicer-1 from pre-miR-307a, generating a longer miRNA isoform with a distinct seed sequence and target specificity. The mouse and human Dicer-binding partner TRBP, a homolog of Loqs-PB, similarly tunes the site of pre-miR-132 cleavage by mammalian Dicer. Thus, Dicer-binding partner proteins can change the choice of cleavage site by Dicer, producing miRNAs with different target specificities than those that would be made by Dicer alone. Examination of Dicer-binding proteins on small RNA profiles of female fly heads, fly ovaries, mouse embryonic fibroblasts, and mouse tail fibroblasts.
2012-12-07 | E-GEOD-37443 | biostudies-arrayexpress
Project description:Drosophila Dicer-1 produces microRNAs (miRNAs) from pre-miRNA, whereas Dicer-2 generates small interfering RNAs (siRNAs) from long dsRNA. loquacious (loqs) encodes three Dicer partner proteins, Loqs-PA, Loqs-PB, and, Loqs-PD, generated by alternative splicing. To understand the function of each Loqs isoform, we constructed loqs isoform-specific rescue flies. Loqs-PD promotes siRNA production in vivo by Dicer-2. Loqs-PA or Loqs-PB is required for viability, but the proteins are not fully redundant: Loqs-PB is required to produce a specific subset of miRNAs. Surprisingly, Loqs-PB tunes the product size cleaved by Dicer-1 from pre-miR-307a, generating a longer miRNA isoform with a distinct seed sequence and target specificity. The mouse and human Dicer-binding partner TRBP, a homolog of Loqs-PB, similarly tunes the site of pre-miR-132 cleavage by mammalian Dicer. Thus, Dicer-binding partner proteins can change the choice of cleavage site by Dicer, producing miRNAs with different target specificities than those that would be made by Dicer alone.
2012-12-07 | GSE37443 | GEO
Project description:The role of RNA silencing as a defense mechanism against viruses remains to be formerly established in mammalian somatic cells. Here, we determined the antiviral properties of human and Drosophila Dicer proteins in a heterologous setup. We expressed human Dicer (hDicer) in Drosophila, and Drosophila Dicer-2 in human cells, and measured the impact on the response to Sindbis virus (SINV) infection. In flies, hDicer presents a low processing activity, but partially rescues a Dcr2 null mutation in flies. Expression of Dicer-2 in HEK293 cells allows the processing of SINV RNA into 21-nt-long small RNAs. Nevertheless, instead of conferring a protective effect against SINV, Dicer-2 expression increases viral replication in HEK293 cells. We present evidence that this effect is due to a competition with the interferon pathway. Our results therefore suggest that adding functionial RNA silencing machinery in IFN-competent differentiated mammalian cells can be detrimental for antiviral defense.
2015-12-28 | GSE62934 | GEO
Project description:In vertebrates, the presence of viral RNA in the cytosol is sensed by members of the RIG-I like receptor (RLR) family , which signal to induce production of type I interferons (IFN). These key anti-viral cytokines act in a paracrine and autocrine manner to induce hundreds of interferon-stimulated genes (ISGs), whose protein products restrict viral entry, replication and budding. ISGs include the RLRs themselves: RIG-I, MDA5 and the least-studied family member, LGP2. In contrast, the IFN system is absent in plants and invertebrates, which defend themselves from viral intruders using RNA interference (RNAi). In RNAi, the endoribonuclease Dicer cleaves virus-derived double stranded RNA (dsRNA) into small interfering RNAs (siRNAs) that target complementary viral RNA for cleavage. Interestingly, the RNAi machinery is conserved in mammals and we have recently demonstrated that it is able to participate in mammalian antiviral defence in conditions in which the IFN system is suppressed. In contrast, when the IFN system is active, one or more ISGs act to mask or suppress antiviral RNAi. Here, we demonstrate that LGP2 constitutes one of the ISGs that can inhibit antiviral RNAi in mammals. We identify Dicer as an LGP2-associated protein and show that LGP2 inhibits Dicer cleavage of dsRNA into siRNAs both in vitro and in vivo. Further, we show that in cells lacking an IFN response, ectopic expression of LGP2 interferes with RNAi-dependent suppression of gene expression. Thus, the inefficiency of RNAi as a mechanism of antiviral defence in mammalian somatic cells can be in part attributed to Dicer inhibition by LGP2 induced by type I IFNs.
2018-01-17 | PXD008364 | Pride
Project description:Mammals have one Dicer gene required for biogenesis of small RNAs in microRNA (miRNA) and RNA interference (RNAi) pathways. Yet, endogenous RNAi is highly active in oocytes but not in somatic cells. Here, we provide a mechanistical explanation for high RNAi activity in mouse oocytes. The main Dicer isoform in oocytes is transcribed from an intronic MT-C retrotransposon, which functions as a promoter of an oocyte-specific Dicer isoform (denoted DicerO). DicerO lacks an N-terminal helicase domain and has a higher cleavage activity than the full-length Dicer from somatic cells. DicerO can rescue the miRNA pathway and, in addition, it efficiently produces small RNAs from long dsRNA substrates. Thus, control of endogenous RNAi activity in mice occurs via alternative Dicer isoform and the phylogenetic origin of DicerO demonstrates evolutionary plasticity of RNA silencing pathways.
2013-11-07 | GSE41207 | GEO
Project description:In mammalian somatic cells, the relative contribution of RNAi and the type I interferon response during viral infection is unclear. The apparent inefficiency of antiviral RNAi might be due to self-limiting properties and mitigating co-factors of the key enzyme Dicer. In particular, the helicase domain of human Dicer appears to be an important restriction factor of its activity. Here, we study the involvement of several helicase-truncated mutants of human Dicer in the antiviral response. All deletion mutants display a PKR-dependent antiviral phenotype against certain viruses, and one of them, Dicer N1, acts in a completely RNAi-independent manner. Transcriptomic analyses show that many genes from the interferon and inflammatory response pathways are upregulated in Dicer N1-expressing cells. We show that some of these genes are controlled by NF-kB and that blocking this pathway abrogates the antiviral phenotype of Dicer N1. Our findings highlight the crosstalk between Dicer, PKR, and the NF-kB pathway, and suggest that human Dicer may have repurposed its helicase domain to prevent basal activation of antiviral and inflammatory pathways.
2024-01-26 | GSE241798 | GEO
Project description:In mammalian somatic cells, the relative contribution of RNAi and the type I interferon response during viral infection is unclear. The apparent inefficiency of antiviral RNAi might be due to self-limiting properties and mitigating co-factors of the key enzyme Dicer. In particular, the helicase domain of human Dicer appears to be an important restriction factor of its activity. Here, we study the involvement of several helicase-truncated mutants of human Dicer in the antiviral response. All deletion mutants display a PKR-dependent antiviral phenotype against certain viruses, and one of them, Dicer N1, acts in a completely RNAi-independent manner. Transcriptomic analyses show that many genes from the interferon and inflammatory response pathways are upregulated in Dicer N1-expressing cells. We show that some of these genes are controlled by NF-kB and that blocking this pathway abrogates the antiviral phenotype of Dicer N1. Our findings highlight the crosstalk between Dicer, PKR, and the NF-kB pathway, and suggest that human Dicer may have repurposed its helicase domain to prevent basal activation of antiviral and inflammatory pathways.
2024-01-26 | GSE241797 | GEO