ISG15 and viral infectious disease: In contrast, deletion of Ubiquitin Specific Peptidase 18 (USP18), the major ISG15 specific protease, which counteracts ISG15 conjugation, increases ISGylation in cells and renders cells more resistant to viral infection in response to IFN (Perng and Lenschow, 2018), suggesting that ISGylation is essential for host defense against viral infections.