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The 3' untranslated region of sindbis virus represses deadenylation of viral transcripts in mosquito and Mammalian cells.

ABSTRACT: The positive-sense transcripts of Sindbis virus (SINV) resemble cellular mRNAs in that they possess a 5' cap and a 3' poly(A) tail. It is likely, therefore, that SINV RNAs must successfully overcome the cytoplasmic mRNA decay machinery of the cell in order to establish an efficient, productive infection. In this study, we have taken advantage of a temperature-sensitive polymerase to shut off viral transcription, and we demonstrate that SINV RNAs are subject to decay during a viral infection in both C6/36 (Aedes albopictus) and baby hamster kidney cells. Interestingly, in contrast to most cellular mRNAs, the decay of SINV RNAs was not initiated by poly(A) tail shortening in either cell line except when most of the 3' untranslated region (UTR) was deleted from the virus. This block in deadenylation of viral transcripts was recapitulated in vitro using C6/36 mosquito cell cytoplasmic extracts. Two distinct regions of the 319-base SINV 3' UTR, the repeat sequence elements and a U-rich domain, were shown to be responsible for mediating the repression of deadenylation of viral mRNAs. Through competition studies performed in parallel with UV cross-linking and functional assays, mosquito cell factors-including a 38-kDa protein-were implicated in the repression of deadenylation mediated by the SINV 3' UTR. This same 38-kDa protein was also implicated in mediating the repression of deadenylation by the 3' UTR of another alphavirus, Venezuelan equine encephalitis virus. In summary, these data provide clear evidence that SINV transcripts do indeed interface with the cellular mRNA decay machinery during an infection and that the virus has evolved a way to avoid the major deadenylation-dependent pathway of mRNA decay.

SUBMITTER: Garneau NL

PROVIDER: S-EPMC2224598 | biostudies-literature | 2008 Jan

REPOSITORIES: biostudies-literature

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The 3' untranslated region of sindbis virus represses deadenylation of viral transcripts in mosquito and Mammalian cells.

Garneau Nicole L NL Sokoloski Kevin J KJ Opyrchal Mateusz M Neff C Preston CP Wilusz Carol J CJ Wilusz Jeffrey J

Journal of virology 20071031 2

The positive-sense transcripts of Sindbis virus (SINV) resemble cellular mRNAs in that they possess a 5' cap and a 3' poly(A) tail. It is likely, therefore, that SINV RNAs must successfully overcome the cytoplasmic mRNA decay machinery of the cell in order to establish an efficient, productive infection. In this study, we have taken advantage of a temperature-sensitive polymerase to shut off viral transcription, and we demonstrate that SINV RNAs are subject to decay during a viral infection in b ...[more]

PMID: 17977976

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Project description:UnlabelledSmall RNAs play a critical role in host-pathogen interaction. Indeed, small RNA-mediated silencing or RNA interference (RNAi) is one of the earliest forms of antiviral immunity. Although it represents the main defense system against viruses in many organisms, the antiviral role of RNAi has not been clearly proven in higher vertebrates. However, it is well established that their response to viral infection relies on the recognition of viral RNAs by host pattern recognition receptors (PRRs) to trigger activation of the interferon pathway. In the present work, we report the existence of a novel small noncoding RNA population produced in mammalian cells upon RNA virus infection. Using Sindbis virus (SINV) as a prototypic arbovirus model, we profiled the small RNA population of infected cells in both human and African green monkey cell lines. Here, we provide evidence for the presence of discrete small RNAs of viral origin that are not associated with the RNA-induced silencing complex (RISC), that are highly expressed and detected by Northern blot analysis, and that accumulate as 21- to 28-nucleotide (nt) species during infection. We report that the cellular antiviral endoribonuclease RNase L cleaves the viral genome, producing in turn the small RNAs. Surprisingly, we uncovered the presence of a modification on the 3'-end nucleotide of SINV-derived viral small RNAs (SvsRNAs) that might be at the origin of their stability. Altogether, our findings show that stable modified small viral RNAs could represent a novel way to modulate host-virus interaction upon SINV infection.ImportanceIn a continuous arms race, viruses have to deal with host antiviral responses in order to successfully establish an infection. In mammalian cells, the host defense mechanism relies on the recognition of viral RNAs, resulting in the activation of type I interferons (IFNs). In turn, the expression of many interferon-stimulated genes (ISGs) is induced to inhibit viral replication. Here we report that the cytoplasmic, interferon-induced, cellular endoribonuclease RNase L is involved in the accumulation of a novel small RNA population of viral origin. These small RNAs are produced upon SINV infection of mammalian cells and are stabilized by a 3'-end modification. Altogether, our findings indicate that in our system RNA silencing is not active against Sindbis virus (SINV) and might open the way to a better understanding of the antiviral response mediated by a novel class of small RNAs.

Dataset Information

The 3' untranslated region of sindbis virus represses deadenylation of viral transcripts in mosquito and Mammalian cells.

Publications

The 3' untranslated region of sindbis virus represses deadenylation of viral transcripts in mosquito and Mammalian cells.

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