TY - JOUR

T1 - Hepatitis C virus RNA is 5'-capped with flavin adenine dinucleotide

AU - Sherwood, Anna V

AU - Rivera-Rangel, Lizandro R

AU - Ryberg, Line A

AU - Larsen, Helena S

AU - Anker, Klara M

AU - Costa, Rui

AU - Vågbø, Cathrine B

AU - Jakljevič, Eva

AU - Pham, Long V

AU - Fernandez-Antunez, Carlota

AU - Indrisiunaite, Gabriele

AU - Podolska-Charlery, Agnieszka

AU - Grothen, Julius E R

AU - Langvad, Nicklas W

AU - Fossat, Nicolas

AU - Offersgaard, Anna

AU - Al-Chaer, Amal

AU - Nielsen, Louise

AU - Kuśnierczyk, Anna

AU - Sølund, Christina

AU - Weis, Nina

AU - Gottwein, Judith M

AU - Holmbeck, Kenn

AU - Bottaro, Sandro

AU - Ramirez, Santseharay

AU - Bukh, Jens

AU - Scheel, Troels K H

AU - Vinther, Jeppe

N1 - © 2023. The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2023

Y1 - 2023

N2 - 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 virus 1,2 (HCV), which causes chronic infection, liver cirrhosis and cancer 3. 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 life 4-8. 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.

AB - 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 virus 1,2 (HCV), which causes chronic infection, liver cirrhosis and cancer 3. 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 life 4-8. 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.

U2 - 10.1038/s41586-023-06301-3

DO - 10.1038/s41586-023-06301-3

M3 - Journal article

C2 - 37407817

VL - 619

SP - 811

EP - 818

JO - Nature

JF - Nature

SN - 0028-0836

ER -