The summaries are free for public
use. The Chronic Liver Disease
Foundation will continue to add and
archive summaries of articles deemed
relevant to CLDF by the Board of
Trustees and its Advisors.
1Section for Computational and RNA Biology, Department of Biology, University of Copenhagen, Copenhagen N, Denmark.
2Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Denmark.
3Copenhagen Hepatitis C Program (CO-HEP), Department of Immunology and Microbiology, University of Copenhagen, Copenhagen N, Denmark.
4Proteomics and Modomics Experimental Core (PROMEC), Norwegian University of Science and Technology and the Central Norway Regional Health Authority, Trondheim, Norway.
5Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Denmark.
6Department of Clinical Medicine, University of Copenhagen, Copenhagen N, Denmark.
7Section for Biomolecular Sciences, Department of Biology, University of Copenhagen, Copenhagen N, Denmark.
8Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Denmark. jbukh@sund.ku.dk.
9Copenhagen Hepatitis C Program (CO-HEP), Department of Immunology and Microbiology, University of Copenhagen, Copenhagen N, Denmark. jbukh@sund.ku.dk.
10Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Denmark. tscheel@sund.ku.dk.
11Copenhagen Hepatitis C Program (CO-HEP), Department of Immunology and Microbiology, University of Copenhagen, Copenhagen N, Denmark. tscheel@sund.ku.dk.
12Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA. tscheel@sund.ku.dk.
13Section for Computational and RNA Biology, Department of Biology, University of Copenhagen, Copenhagen N, Denmark. jvinther@bio.ku.dk.
#Contributed equally.
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.
Stay Informed!
