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FP7

DEGRAVIR Report Summary

Project ID: 622142
Funded under: FP7-PEOPLE
Country: France

Final Report Summary - DEGRAVIR (SUPPRESSION OF RNA DEGRADATION BY PLANT PARARETROVIRUS: HIJACKING OF DECAPPING COMPLEXES)

During pathogenesis, viruses hijack the host cellular machinery to access the molecules and sub-cellular structures required for infection. Since plant viruses are able to subvert cellular pathways and suppress defence responses in order to spread infection, they represent essential keys to interfere with cellular control. Gene expression in eukaryotes is a tightly orchestrated process that includes multiple levels of regulation from transcription to protein stability. Among these regulatory mechanisms, mRNA decay plays an important role as a very sensitive and dynamic system of gene expression modulation via alteration of mRNA stability in response to environmental, developmental and physiological signals. Until now, there is no evidence that viruses can evade host defence by integration into RNA decay machineries such as decapping, deadenylation or nonsense-mediated decay (NMD) complexes in order to block mRNA degradation. A set of principles of induction, evasion, and suppression define NMD as a general viral restriction mechanism in plants that also likely operates in animals.

Cauliflower mosaic virus (CaMV) is a plant pararetrovirus, the type member of the Caulimovirus genus of Caulimoviridae. Our project revealed that the CaMV multifunctional viral protein—translation transactivator/ viroplasmin (TAV)—is famous for its ability to overcome cellular barriers to polycistronic translation in eukaryotes—functions as a suppressor of cellular mRNA turnover, particularly stabilizing mRNAs harboring premature stop codons that are degraded via nonsense mediated decay (NMD) mechanisms. Here, we uncovered that viral pathogen CaMV can recognize and stabilize RNAs with internal termination codons, but not with long 3’ UTRs—both are substrates for nonsense-mediated decay (NMD), and thus down regulate a host RNA quality control mechanism.

NMD serves as a prequel to mRNA decapping followed by 5’-3’ exonucleolytic degradation. Strikingly, we discovered that TAV suppresses NMD by targeting the decapping machinery, raising a question about a strong link between the decapping complex and the NMD machinery. TAV interacts or integrates within the decapping machinery via binding its scaffold protein VARICOSE (VCS; Xu et al., et al., 2006) that is at the heard of the complex linking two other decapping proteins—DCP1 and DCP2. Mapping of VCS and TAV interaction domains allowed us to demonstrate the critical significance of both proteins in suppression of NMD decay by employing the deletion mutagenesis and in patch agroinfiltration assay on N. benthamiana leaves. The TAV domain (so called D3 motif) that is responsible for TAV function in NMD suppression is remarkably conserved between CaMV and other related pararetroviruses, indicating that TAV-related proteins from CaMV related pararetroviruses would function as suppressors of cellular and viral RNA degradation by NMD. Functional significance of our results is underlined by the fact that the CaMV mutant virus, carrying a D3 deletion within TAV accumulates at low titers in systemic leaves of A. thaliana plants, albeit developing no disease symptoms. As expected, TAV co-localizes with the decapping complex—VCS, DCP1 and DCP2—in N. benthamiana stress granules, so-called P-bodies. We expect that VCS can ensure TAV entry into P-bodies.

These studies revealed that viral protein-based suppression of RNA degradation is a universal mechanism employed by plant pararetroviruses and, perhaps, also animal retroviruses. This will help to design new strategies to counteract mRNA degradation in general using plant pararetroviral vector. We propose that CaMV virus via its essential protein TAV can interfere with the nonsense mediated mRNA decay by targeting the mRNA decapping complex. The identification of cellular and CaMV decay pathways and factors involved should provide us with information on how mRNA degradation pathways are involved in antiviral defence. Our data indicate that the essential role of TAV in polycistronic RNA translation is strengthened by a role in control of mRNA NMD pathways.

NMD also operates in natural infection contexts, and while some viruses have evolved genome expression strategies to overcome this process altogether, the virulence of NMD-activating viruses entails their ability to directly suppress NMD, particularly in our case, when NMD suppression is achieve via suppression of the decapping mechanism.

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Contact

Gaëlle BUJAN, (Déléguée régionale)
Tel.: +33 3 88 10 63 10
E-mail
Record Number: 189489 / Last updated on: 2016-10-06
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