SUMMARY
The RNA modification N6-methyladenosine (m6A) post-transcriptionally regulates RNA function. The cellular machinery that controls m6A includes methyltransferases and demethylases that add or remove this modification as well as m6A-binding YTHDF proteins that promote the translation or degradation of m6A-modified mRNA. We demonstrate that m6A modulates infection by hepatitis C virus (HCV). Depletion of m6A-methyltransferases or an m6A-demethylase respectively increases and decreases infectious HCV particle production. During HCV infection, YTHDF proteins relocalize to lipid droplets, sites of viral assembly, and their depletion increases infectious viral particles. We further mapped m6A sites across the HCV genome and determine that inactivating m6A in one viral genomic region increases viral titer without affecting RNA replication. Additional mapping of m6A on the RNA genomes of other Flaviviridae, including dengue, Zika, yellow fever, and West Nile virus, identifies conserved regions modified by m6A. Together, this work identifies m6A as a conserved regulatory mark across Flaviviridae genomes.
RNA virus infection is sensed in the cytoplasm by the retinoic acid-inducible gene I (RIG-I)-like receptors. These proteins signal through the host adaptor protein MAVS to trigger the antiviral innate immune response. Here, we describe how MAVS subcellular localization impacts its function and the regulation underlying MAVS signaling. We propose a model to describe how the coordination of MAVS functions at the interface between the mitochondria and the mitochondrion-associated endoplasmic reticulum (ER) membrane programs antiviral signaling.
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