RIG-I Recognizes the 5′ Region of Dengue and Zika Virus Genomes

Abstract

Summary: The flavivirus genus comprises major human pathogens, such as Dengue (DENV) and Zika (ZIKV) viruses. RIG-I and MDA5 are key cytoplasmic pathogen recognition receptors that are implicated in detecting viral RNAs. Here, we show that RNAs that co-purified with RIG-I during DENV infection are immuno-stimulatory, whereas RNAs bound to MDA5 are not. An affinity purification method combined with next-generation sequencing (NGS) revealed that the 5′ region of the DENV genome is recognized by RIG-I. No DENV RNA was bound to MDA5. In vitro production of fragments of the DENV genome confirmed the NGS data and revealed that the 5′ end of the genome, when bearing 5′-triphosphates, is the RIG-I ligand. The 5′ region of the ZIKV genome is also a RIG-I agonist. We propose that RIG-I binds to the highly structured and conserved 5′ region of flavivirus nascent transcripts before capping and that this mechanism leads to interferon secretion by infected cells. : Using a panel of techniques, including a ribonucleoproteomic approach based on tagged protein affinity purification combined with next-generation sequencing, Chazal et al. show that the cytoplasmic sensor RIG-I plays a key role in cellular defense against Dengue and Zika viruses. Keywords: flavivirus, Dengue virus, Zika virus, innate immunity, antiviral immunity, pathogen recognition receptors, RIG-I, MDA5, riboproteomic approach