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Respiratory syncytial virus M2-1 protein associates non-specifically with viral messenger RNA and with specific cellular messenger RNA transcripts.

ABSTRACT: Respiratory syncytial virus (RSV) is a major cause of respiratory disease in infants and the elderly. RSV is a non-segmented negative strand RNA virus. The viral M2-1 protein plays a key role in viral transcription, serving as an elongation factor to enable synthesis of full-length mRNAs. M2-1 contains an unusual CCCH zinc-finger motif that is conserved in the related human metapneumovirus M2-1 protein and filovirus VP30 proteins. Previous biochemical studies have suggested that RSV M2-1 might bind to specific virus RNA sequences, such as the transcription gene end signals or poly A tails, but there was no clear consensus on what RSV sequences it binds. To determine if M2-1 binds to specific RSV RNA sequences during infection, we mapped points of M2-1:RNA interactions in RSV-infected cells at 8 and 18 hours post infection using crosslinking immunoprecipitation with RNA sequencing (CLIP-Seq). This analysis revealed that M2-1 interacts specifically with positive sense RSV RNA, but not negative sense genome RNA. It also showed that M2-1 makes contacts along the length of each viral mRNA, indicating that M2-1 functions as a component of the transcriptase complex, transiently associating with nascent mRNA being extruded from the polymerase. In addition, we found that M2-1 binds specific cellular mRNAs. In contrast to the situation with RSV mRNA, M2-1 binds discrete sites within cellular mRNAs, with a preference for A/U rich sequences. These results suggest that in addition to its previously described role in transcription elongation, M2-1 might have an additional role involving cellular RNA interactions.

SUBMITTER: Braun MR

PROVIDER: S-EPMC8162694 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Circular RNAs (circRNAs) are a new class of noncoding RNAs that have gained increased attention. DNA virus infections have been reported to induce modifications in cellular circRNA transcriptomes and express viral circRNAs. However, the identification and expression of cellular and viral circRNAs are unknown in the context of respiratory syncytial virus (RSV), a human RNA virus with no effective treatments or vaccines. Here, we report a comprehensive identification of the cellular and viral circRNAs induced by RSV infection in A549 cells with high-throughput sequencing. In total, 53,719 cellular circRNAs and 2,280 differentially expressed cellular circRNAs were identified. Trend analysis further identified three significant expression pattern clusters, which were related to the antiviral immune response according to gene enrichment analysis. Subsequent results showed that not only RSV infection but also poly(I·C) treatment and another RNA virus infection induced the upregulation of the top 10 circRNAs from the focused cluster. The top 10 circRNAs generally inhibit RSV replication in turn. Moreover, 1,254 viral circRNAs were identified by the same circRNA sequencing. The induced expression of viral circRNAs by RSV infection was found not only in A549 cells but also in HEp-2 cells. Additionally, we profiled the general characteristics of both cellular and viral circRNAs such as back-splicing signals, etc. Collectively, RSV infection induced the differential expression of cellular circRNAs, some of which affected RSV infection, and RSV also expressed viral circRNAs. Our study reveals novel layers of host-RSV interactions and identifies cellular or viral circRNAs that may be novel therapeutic targets or biomarkers. IMPORTANCE Noncoding RNAs (ncRNAs) demonstrate substantial roles in cell-virus interactions. Circular RNAs (circRNAs) are a newly identified class of ncRNAs that have gained increased attention recently. DNA virus infections have been reported to induce modifications in cellular circRNA transcriptomes and express viral circRNAs. However, the identification and expression of cellular and viral circRNAs are unknown in the context of respiratory syncytial virus (RSV), a human RNA virus with no effective treatments or vaccines. Here, we report a comprehensive identification of the cellular and viral circRNAs induced by RSV infection by high-throughput sequencing. We revealed that RSV infection induces the differential expression of cellular circRNAs, some of which affected RSV infection, and that RSV also expresses viral circRNAs. Our study reveals novel layers of host-RSV interactions and identifies cellular or viral circRNAs that may be novel therapeutic targets or biomarkers.

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Respiratory syncytial virus M2-1 protein associates non-specifically with viral messenger RNA and with specific cellular messenger RNA transcripts.

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