Interferon-stimulated expression and conjugation of the ubiquitin-like modifier ISG15 restricts replication of several viruses. Here, we established complete E1-activating, E2-conjugating, and E3 ligase-dependent expression systems for assaying both human and mouse ISGylation. We confirm that human HerC5, but not human HerC6, has ISG15 E3 ligase activity and identify mouse HerC6 as a bona fide ISG15 E3 ligase. Furthermore, we demonstrate that influenza B virus NS1 protein potently antagonizes human but not mouse ISGylation, a property dependent on B/NS1 binding the N-terminal domain of human but not mouse ISG15. Using chimeric human/mouse ISG15 constructs, we show that the B/NS1:ISG15 interaction is both necessary and sufficient to inhibit ISGylation regardless of the ligation machinery used. Inability to block ISGylation in certain species may contribute to limiting influenza B virus host range. Copyright

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Versteeg, G.A., Hale, B.G., van Boheemen, S., Wolff, T., Lenschow, D.J., & García-Sastre, A.. (2010). Species-specific antagonism of host ISGylation by the influenza B virus NS1 protein. Journal of Virology, 84(10), 5423–5430. doi:10.1128/JVI.02395-09