Journal
GENES & DEVELOPMENT
Volume 30, Issue 14, Pages 1658-1670Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.284604.116
Keywords
RNA degradation; TRAMP; exosome; antiviral; arbovirus; intrinsic immunity
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Funding
- National Institute of Health [R01AI074951, U54AI057168, R01AI095500, R00GM104166, T32AI007324]
- Burroughs Wellcome Investigators in the Pathogenesis of Infectious Disease Award
- Lundbeck Foundation [R198-2015-172] Funding Source: researchfish
- Novo Nordisk Fonden [NNF15OC0017010] Funding Source: researchfish
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RNA degradation is tightly regulated to selectively target aberrant RNAs, including viral RNA, but this regulation is incompletely understood. Through RNAi screening in Drosophila cells, we identified the 3'-to-5' RNA exosome and two components of the exosome cofactor TRAMP (Trf4/5-Air1/2-Mtr4 polyadenylation) complex, dMtr4 and dZcchc7, as antiviral against a panel of RNA viruses. We extended our studies to human orthologs and found that the exosome as well as TRAMP components hMTR4 and hZCCHC7 are antiviral. While hMTR4 and hZCCHC7 are normally nuclear, infection by cytoplasmic RNA viruses induces their export, forming a cytoplasmic complex that specifically recognizes and induces degradation of viral mRNAs. Furthermore, the 3' untranslated region (UTR) of bunyaviral mRNA is sufficient to confer virus-induced exosomal degradation. Altogether, our results reveal that signals from viral infection repurpose TRAMP components to a cytoplasmic surveillance role where they selectively engage viral RNAs for degradation to restrict a broad range of viruses.
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