Lai C, Struckhoff JJ, Schneider J, Martinéz-Sobrido L, Wolff T et al. (2008): Mice lacking the ISG15 E1 enzyme, UbE1L, demonstrate increased susceptibility to both mouse adapted and non-adapted influenza B virus infection
J. Virol.: Epub 2008 Nov 12.

ISG15 functions as a critical antiviral molecule against influenza virus, with infection inducing both the ISGylation of target proteins and the production of free ISG15.  Here, we report that mice lacking the ISG15 E1 enzyme, UbE1L, are unable to form ISG15 conjugates, and similar to ISG15-/- mice, display increased susceptibility to influenza B virus, including non-mouse adapted strains. Mutating the NS1 protein in a recombinant influenza B virus, so that it no longer blocked ISG15 conjugation, attenuated viral growth in a human epithelial cell line. Therefore, the conjugation of ISG15 to target proteins is critical to its antiviral activity against influenza virus.