Interference with host ISGylation by viral deubiquitinating enzymes has been implicated in virus virulence as well; for example, partial relief of the ISG15-antagonistic function effect of porcine reproductive and respiratory syndrome virus (PRRSV) non-structural protein 2 (NSP 2) ovarian tumor (OTU) protease domain produced a recombinant virus with reduced virulence in vivo [34]. Here, ISG15 is linked to ovarian neoplasm.