Species-specific antagonism of host ISGylation by the influenza B virus NS1 protein.
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.
Versteeg
Gijs A
GA
Department of Microbiology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.
Hale
Benjamin G
BG
van Boheemen
Sander
S
Wolff
Thorsten
T
Lenschow
Deborah J
DJ
García-Sastre
Adolfo
A
D000595:Amino Acid Sequence; D000818:Animals; D016207:Cytokines / Q000037:antagonists & inhibitors*; D006801:Humans; D009981:Influenza B virus / Q000276:immunology* / Q000472:pathogenicity*; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology; D051379:Mice; D008969:Molecular Sequence Data; D011485:Protein Binding; D016415:Sequence Alignment; D044767:Ubiquitin-Protein Ligases / Q000276:immunology; D014452:Ubiquitins / Q000037:antagonists & inhibitors*; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D037521:Virulence Factors / Q000378:metabolism*
D016207:Cytokines; C489550:G1p2 protein, mouse; C402395:HERC5 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D014452:Ubiquitins; D017361:Viral Nonstructural Proteins; D037521:Virulence Factors; C074034:ISG15 protein, human; C502269:HERC6 protein, human; D044767:Ubiquitin-Protein Ligases