{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Sherwood AV"],"funding":["European Research Council","Novo Nordisk Fonden"],"pagination":["811-818"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC7616780"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["619(7971)"],"pubmed_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 virus<sup>1,2</sup> (HCV), which causes chronic infection, liver cirrhosis and cancer<sup>3</sup>. 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<sup>4-8</sup>. 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."],"journal":["Nature"],"pubmed_title":["Hepatitis C virus RNA is 5'-capped with flavin adenine dinucleotide."],"pmcid":["PMC7616780"],"funding_grant_id":["NNF18OC0055462","NNF18OC0054518","802899","NNF19OC0058443","NNF18OC0052354","NNF22SA0078213"],"pubmed_authors":["Rivera-Rangel LR","Langvad NW","Anker KM","Jakljevic E","Fossat N","Al-Chaer A","Scheel TKH","Pham LV","Fernandez-Antunez C","Kusnierczyk A","Solund C","Podolska-Charlery A","Nielsen L","Bottaro S","Sherwood AV","Ryberg LA","Gottwein JM","Larsen HS","Offersgaard A","Vinther J","Ramirez S","Vagbo CB","Holmbeck K","Grothen JER","Costa R","Weis N","Bukh J","Indrisiunaite G"],"additional_accession":[]},"is_claimable":false,"name":"Hepatitis C virus RNA is 5'-capped with flavin adenine dinucleotide.","description":"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<sup>1,2</sup> (HCV), which causes chronic infection, liver cirrhosis and cancer<sup>3</sup>. 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<sup>4-8</sup>. 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.","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Jul","modification":"2026-06-02T11:37:18.153Z","creation":"2025-04-21T21:50:01.124Z"},"accession":"S-EPMC7616780","cross_references":{"pubmed":["37407817"],"doi":["10.1038/s41586-023-06301-3"]}}