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 -