Interferon-stimulated gene LY6E enhances entry of diverse RNA viruses

Abstract The type I interferon (IFN) response is the primary cellular defense mechanism against viruses. IFN protects against viral infection by activating the expression of hundreds of interferon-stimulated genes (ISGs), some of which have potent antiviral effector activity. Our recent screening efforts to identify novel antiviral ISGs unexpectedly uncovered a small subset of genes that enhanced viral infectivity. The goals of this project are to characterize the mechanism of LY6E, an ISG that enhanced unrelated viruses from multiple families. Here we show that ectopic expression of LY6E enhances cellular infection by a subset of enveloped RNA viruses from diverse families, including yellow fever virus, influenza A virus, vesicular stomatitis virus, and O’nyong’nyong virus. The enhancement phenotype is dependent on cell lineage, with the strongest effects seen in fibroblast and monocytic cell lines. Ablation of endogenous LY6E by CRISPR/Cas9 reduces but does not abrogate viral infectivity, indicating that LY6E is important for optimal infection. Loss of LY6E does not alter antiviral protection by IFN, suggesting that the enhancing effects may be direct. Mechanistic studies reveal that LY6E enhances infectivity at an early step in the viral life cycle, after viral binding but prior to the establishment of replication. Visualization of single-cell infections by ImageStream confirms that LY6E enhances viral entry. We conclude that LY6E enhances viral uptake at the population level, which may be important for initiation of the cell-mediated antiviral immune response. Understanding the mechanism and significance of LY6E to the antiviral interferon response may aid in the development of novel antiviral therapeutics.