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N6-methyladenosine modification is not a general trait of viral RNA genomes [Dengue]

ABSTRACT: N6-methyladenosine (m6A), the most common internal RNA modification in eukaryotic mRNAs, is described to be abundantly present in the genomes of cytoplasmic-replicating RNA viruses. Yet, how the host nuclear m6A writer has access to the viral RNAs in the cytoplasm and what are the associated biological consequences remain unknown. Here, we comprehensively addressed these questions by combining antibody-dependent (m6A-seq) and antibody-independent (SELECT and nanopore direct RNA sequencing) methods on the cytoplasmic-replicating Chikungunya virus (CHIKV) RNA, and found no evidence of m6A modifications. Moreover, depletion of m6A modification machinery components did not affect CHIKV infection, and CHIKV infection did not alter their cellular localization. Consistent with these observations, no m6A modifications were found in the RNA genome of the dengue virus (DENV), another cytoplasmic-replicating virus. Our results challenge the idea that m6A modification is a general trait of cytoplasmic-replicating RNA viruses and stress the need of confirming antibody-dependent detection of m6A modifications with orthogonal antibody-independent methods.

ORGANISM(S): Homo sapiens Dengue virus

PROVIDER: GSE231738 | GEO | 2024/01/23

REPOSITORIES: GEO

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N6-methyladenosine modification is not a general trait of viral RNA genomes [CHIKV]

Project description:N6-methyladenosine (m6A), the most common internal RNA modification in eukaryotic mRNAs, is described to be abundantly present in the genomes of cytoplasmic-replicating RNA viruses. Yet, how the host nuclear m6A writer has access to the viral RNAs in the cytoplasm and what are the associated biological consequences remain unknown. Here, we comprehensively addressed these questions by combining antibody-dependent (m6A-seq) and antibody-independent (SELECT and nanopore direct RNA sequencing) methods on the cytoplasmic-replicating Chikungunya virus (CHIKV) RNA, and found no evidence of m6A modifications. Moreover, depletion of m6A modification machinery components did not affect CHIKV infection, and CHIKV infection did not alter their cellular localization. Consistent with these observations, no m6A modifications were found in the RNA genome of the dengue virus (DENV), another cytoplasmic-replicating virus. Our results challenge the idea that m6A modification is a general trait of cytoplasmic-replicating RNA viruses and stress the need of confirming antibody-dependent detection of m6A modifications with orthogonal antibody-independent methods.

2024-01-23 | GSE231737 | GEO

N6-methyladenosine modification is not a general trait of positive-sense RNA viral genomes

Project description:<p>Despite the nuclear localization of the m6A machinery, the genomes of multiple exclusively-cytoplasmic RNA viruses, such as chikungunya (CHIKV) and dengue (DENV), are reported to be extensively m6A-modified. However, these findings are mostly based on m6A-seq, an antibody-dependent technique with a high rate of false positives. Here, we addressed the presence of m6A in CHIKV and DENV RNAs. For this, we combined m6A-seq and the antibody-independent SELECT and nanopore direct RNA sequencing techniques with functional, molecular, and mutagenesis studies. Following this comprehensive analysis, we found no evidence of m6A modification in CHIKV or DENV transcripts. Furthermore, depletion of key components of the host m6A machinery did not affect CHIKV or DENV infection. Moreover, CHIKV or DENV infection had no effect on the m6A machinery’s localization. Our results challenge the prevailing notion that m6A modification is a general feature of cytoplasmic RNA viruses and underscore the importance of validating RNA modifications with orthogonal approaches.</p>

2024-01-25 | MTBLS6978 | MetaboLights

Virus-induced codon-specific reprogramming to favor viral RNA translation

Project description:How viruses, such as the emerging mosquito-borne Chikungunya virus (CHIKV), express their genomes at high levels despite an enrichment in suboptimal codons remains a puzzling question. By integrating subcellular fractionation and transcriptome-wide analyses of translation in CHIKV-infected human cells, we demonstrate an unanticipated virus-induced reprogramming of the host translation machinery to favor translation of viral RNA over cellular genes featuring optimal codon usage. This reprogramming was specifically apparent at the endoplasmic reticulum (ER), the preferred translation compartment of CHIKV RNA, and it is mediated by the wobble uridine 34 tRNA modification enzyme KIAA1456 whose expression is enhanced upon viral infection. Since KIAA1456 itself is encoded by a CHIKV-like codon usage, infection triggers a positive feed-back loop that ensures efficient virus protein production. Our findings demonstrate an unprecedented interplay of viruses with the host tRNA epitranscriptome to favor viral protein expression.

2022-06-17 | GSE143390 | GEO

The cytoplasmic LSm1-7 and nuclear LSm2-8 complexes exert opposite effects on Hepatitis B virus biosynthesis and interferon response

Project description:Viruses employ various strategies to evade innate immunity. Despite many studies on host or viral gene expression, how the cellular proteome responds to internal or external cues, has not been fully investigated. Using a Hepatitis B Virus (HBV) replication model, we performed proteomic analyses of HBV-replicating cells in G1/S and G2/M phases, as a function of IFN-alpha, providing specific information of how HBV infection, in combination with IFN-alpha, alters the hepatocyte proteome. We identified the conserved LSm (Like-Sm1-8) proteins were differentially expressed as a function of HBV replication and IFN-alpha. Specifically, in G2/M, IFN-alpha increased protein level of LSm1, the unique subunit of cytoplasmic LSm1-7 complex involved in mRNA decay. By contrast, IFN-alpha decreased LSm8, the unique subunit of nuclear LSm2-8 complex, a chaperone of U6 spliceosomal RNA. These results suggest cytoplasmic LSm1-7 has antiviral role, whereas nuclear LSm2-8 complex is pro-viral. Employing HBV replication and infection models, siRNA-mediated knockdown of LSm1 increased the level of all viral RNAs. Conversely, knockdown of LSm8 reduced viral RNA levels, dependent on N6-adenosine methylation (m6A) of the epsilon stem-loop at the 5 end of pre-Core/pregenomic (preC/pg) RNA. Methylated RNA immunoprecipitation (MeRIP) assays demonstrated reduced viral RNA methylation upon LSm8 knockdown, dependent on the m6A modification, suggesting the LSm2-8 complex has a role in mediating this modification. Interestingly, splicing inhibitor Cp028 acting upstream of LSm2-8 complex, suppressed levels of viral RNAs without reducing the m6A modification. This observation suggests Cp028 has novel antiviral effects, likely potentiating IFN-alpha -mediated suppression of HBV biosynthesis.

2022-06-03 | MSV000089600 | MassIVE

The novel lncRNA ALPHA specifically targets chikungunya virus to control infection

Project description:We set out to determine whether lncRNAs can contribute to additional antiviral immune strategies independently of canonical innate signaling. High-throughput genetic screening of 2200 human lncRNAs led to the identification of the cytoplasmic antiviral lncRNA Antiviral LncRNA Prohibiting Human Alphaviruses (ALPHA) which is transcriptionally induced by alphaviruses and functions independently of IFN to specifically inhibit the replication of CHIKV and its closest relative, O’nyong’nyong virus (ONNV), but not other viruses. Furthermore, we showed that ALPHA interacts with CHIKV genomic RNA and restrains viral RNA replication. Together, our findings reveal that ALPHA and potentially other lncRNAs can mediate non-canonical antiviral immune responses against specific viral pathogens.

2022-09-13 | GSE184306 | GEO

Altered m6A Modification of Specific Cellular Transcripts Affects Flaviviridae Infection

Project description:The RNA modification N6-methyladenosine (m6A) can modulate mRNA fate and thus affect many biological processes. We analyzed m6A modification across the transcriptome following infection by dengue virus (DENV), Zika virus (ZIKV), West Nile virus (WNV), and hepatitis C virus (HCV). We found that infection by these viruses in the Flaviviridae family alters m6A modification of specific cellular transcripts, including RIOK3 and CIRBP. During viral infection, the addition of m6A to RIOK3 promotes its translation, while loss of m6A in CIRBP promotes alternative splicing. Importantly, we found that viral activation of innate immune sensing or the endoplasmic reticulum (ER) stress response contributes to the changes in m6A modification in RIOK3 and CIRBP, respectively. Further, several transcripts with infection-altered m6A profiles, including RIOK3 and CIRBP, encode proteins that influence DENV, ZIKV, and HCV infection. Overall, this work reveals that cellular signaling pathways activated during viral infection lead to alterations in m6A modification of host mRNAs to regulate infection.

2019-10-11 | GSE138730 | GEO

Discovery of Widespread Host Protein Interactions with the Pre-Replicated Genome of CHIKV using VIR-CLASP

Project description:The pioneer interactions between incoming viral RNA genomes and host proteins are crucial to infection and immune response. Until now, the ability to study these events was lacking. We developed VIR-CLASP (VIRal Cross-Linking And Solid-phase Purification) to characterize the earliest interactions between viral RNA and cellular proteins. We investigated the infection of human cells using Chikungunya virus (CHIKV) and Influenza A virus and identified hundreds of direct RNA-protein interactions. Here, we validate the biological impact of three protein classes that bind CHIKV RNA within minutes of infection. We find CHIKV RNA binds and hijacks the lipid-modifying enzyme FASN for pro-viral activity. We show that CHIKV genomes are N6-methyladenosine modified and that YTHDF1 binds and suppresses its replication. Finally, we find that the innate immune DNA sensor IFI16 associates with CHIKV RNA, reducing viral replication and maturation. Our findings have direct applicability to the investigation of potentially all RNA viruses.

2020-05-11 | PXD015863 | Pride

N6-methyladenosine is a molecular signature for discrimination of self and non-self RNA by cytoplasmic RNA sensor RIG-I

Project description:Internal N6-methyladenosine (m6A) modification of RNA is one of the most common and abundant modifications in eukaryotic cells as well as in viruses. However, the biological role(s) of RNA m6A in virus-host interaction remains elusive. Using human metapneumovirus (hMPV), a medically important non-segmented negative-sense RNA virus as a model, we demonstrate that m6A serves as a molecular marker for innate immune discrimination self and nonself RNAs. We show that hMPV RNAs are m6A methylated and that viral m6A methylation promotes hMPV replication and gene expression. HMPV infection leads to differential expression of interferon-related genes involved in innate immune signaling pathways. Inactivating these m6A sites with synonymous mutations resulted in m6A deficient recombinant hMPVs that induced significantly higher expression of type I interferon that restricted viral replication. Notably, the induction of type I interferons by m6A-deficient rhMPVs and virion RNA was dependent on the cytoplasmic RNA sensor RIG-I, not MDA5. Mechanistically, m6A-deficient virion RNA induces higher expression of RIG-I, enhances its binding affinity to RIG-I, and facilitates the conformational change of RIG-I, leading to enhanced induction of type I IFN expression. The replication of m6A-deficient rhMPVs was attenuated in wild type A459 cells but was restored in cells knocked out for RIG-I and MAVS. Furthermore, m6A-deficient rhMPVs triggered higher type I interferon in vivo and were significantly attenuated in the lower respiratory tract yet retained high immunogenicity in cotton rats. Collectively, our results highlight that (i) virus acquires m6A in their RNAs as a means of mimicking cellular RNA to avoid the detection by innate immunity; and (ii) viral m6A RNA can serve as a novel target to attenuate hMPV for vaccine purposes.

2019-10-18 | GSE136139 | GEO

Alphaherpesviruses remodel the cellular transcriptome to deplete m6A-containing transcripts

Project description:Virus infections are accompanied by major transcriptional changes in the host cell. We systematically investigated whether infection with viruses from different virus families specifically affects transcripts containing m6A, the most common internal modification of mRNA. Alphaherpesviruses were found to extensively alter m6A processing of infected cells.

2022-05-25 | GSE201012 | GEO

MeRIP-seq for host response to Flaviviridae infection

Project description:The modification N6-methyladenosine (m6A) affects rates of translation and degradation of mRNA transcripts. We analyzed m6A across the transcriptome following infection by dengue virus (DENV), Zika virus (ZIKV), West Nile virus (WNV), and hepatitis C virus (HCV) using MeRIP-seq. We used the uninfected replicates, among which we would expect little biological variation in methylation, as negative controls to validate statistical methods for the detection of m6A changes in MeRIP-seq data. Applying validated statistical methods, we found that innate immune response to Flaviviridae viruses alters m6A modification of specific cellular transcripts compared to uninfected controls. Finally, we find that these changes in m6A can in turn affect splicing or translation of genes relevant to infection.

2019-05-09 | GSE130891 | GEO

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