Hepatitis C virus RNA is 5'-capped with flavin adenine dinucleotide

Anna V Sherwood, Lizandro R Rivera-Rangel, Line A Ryberg, Helena S Larsen, Klara M Anker, Rui Costa, Cathrine B Vågbø, Eva Jakljevič, Long V Pham, Carlota Fernandez-Antunez, Gabriele Indrisiunaite, Agnieszka Podolska-Charlery, Julius E R Grothen, Nicklas W Langvad, Nicolas Fossat, Anna Offersgaard, Amal Al-Chaer, Louise Nielsen, Anna Kuśnierczyk, Christina SølundNina Weis, Judith M Gottwein, Kenn Holmbeck, Sandro Bottaro, Santseharay Ramirez, Jens Bukh, Troels K H Scheel, Jeppe Vinther

8 Citationer (Scopus)

Abstract

RNA viruses have evolved elaborate strategies to protect their genomes, including 5' capping. However, until now no RNA 5' cap has been identified for hepatitis C virus1,2 (HCV), which causes chronic infection, liver cirrhosis and cancer3. Here we demonstrate that the cellular metabolite flavin adenine dinucleotide (FAD) is used as a non-canonical initiating nucleotide by the viral RNA-dependent RNA polymerase, resulting in a 5'-FAD cap on the HCV RNA. The HCV FAD-capping frequency is around 75%, which is the highest observed for any RNA metabolite cap across all kingdoms of life4-8. FAD capping is conserved among HCV isolates for the replication-intermediate negative strand and partially for the positive strand. It is also observed in vivo on HCV RNA isolated from patient samples and from the liver and serum of a human liver chimeric mouse model. Furthermore, we show that 5'-FAD capping protects RNA from RIG-I mediated innate immune recognition but does not stabilize the HCV RNA. These results establish capping with cellular metabolites as a novel viral RNA-capping strategy, which could be used by other viruses and affect anti-viral treatment outcomes and persistence of infection.

OriginalsprogEngelsk
TidsskriftNature
Vol/bind619
Udgave nummer7971
Sider (fra-til)811-818
Antal sider8
ISSN0028-0836
DOI
StatusUdgivet - jul. 2023

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