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Discovery of 5’ NAD capped viral RNAs reveals evolutionary divergent 5’ metabolite capping across hepaciviruses

Year: 2026
Type: article
Abstract: Hepatitis C virus (HCV), an important pathogen and prototype hepacivirus, 5’ caps its RNA with flavin adenine dinucleotide (FAD); no other 5’ metabolite capped viral RNAs have been identified. Here, we establish NADzymeID, allowing specific identification of 5’ nicotinamide adenine dinucleotide (NAD). Using NADzymeID, we find that Norway rat hepacivirus 1 (NrHV-1) and related hepaciviruses use 5’ NAD capping, whereas the closest relatives of HCV use 5’ FAD, thereby revealing evolutionary divergence of 5’ capping. NrHV-1 replication is attenuated in absence of NAD, and NrHV-1 is cleared more rapidly in mice with reduced intrahepatic NAD levels. As observed for 5’ FAD, 5’ NAD protects viral RNA from RIG-I mediated innate immune sensing. Thus, despite evolutionary divergence, metabolite capping generally confers evasion of innate immune responses. These represent the first examples of 5’ NAD capping for viruses, providing tools also to investigate the elusive function of cellular 5’ metabolite caps. Larsen et al. demonstrate that one clade of hepaciviruses use FAD and the other use NAD to protect their RNA genomes by 5’ metabolite capping and facilitate innate immune evasion. The study provides the first examples of viral 5’NAD RNA capping.
DOI: 10.1038/s41467-026-74886-0
Authors: Helena S. Larsen, Anna V. Sherwood, Lizandro R. Rivera-Rangel, Line A. Ryberg, Paula H. Faller, Caroline E. Thorselius, Cathrine B. Vågbø, Kenn Holmbeck, Sonja Fernbach, Sabina Chubanava, Anna S. Hassing, Eva Jakljevič, Nicola Rose, Helena D. Tjørnelund-Sjursen, Raphael Wolfisberg, Matthew J. Kennedy, Louise Nielsen, Amal Al-Chaer, Santseharay Ramirez, Jonas T. Treebak, Jens Bukh, Jeppe Vinther, Troels K. H. Scheel
Institutions: University of Copenhagen, Hvidovre Hospital, Copenhagen University Hospital, Norwegian University of Science and Technology, Central Norway Regional Health Authority, Novo Nordisk Foundation Center for Basic Metabolic Research, Medicines and Healthcare products Regulatory Agency
Language: English
Subfield: Immunology
Open Access status: gold
Estimated APC paid: $6,990
Funders: National Science Foundation, McGill University, Norges Teknisk-Naturvitenskapelige Universitet, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Gentofte Hospital, Ministerio de Economía y Competitividad, Novo Nordisk, Helse Midt-Norge, Norges Forskningsråd, Novo Nordisk Foundation Center for Basic Metabolic Research, Centro de Investigação em Biomedicina
OpenAlex ID: W7166577705
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