Catalysis of the transfer of a ISG15 to a substrate protein via the reaction X-ISG15 + S = X + S-ISG15, where X is either an E2 or E3 enzyme, the X-ISG15 linkage is a thioester bond, and the S-ISG15 linkage is an isopeptide bond between the C-terminal amino acid of ISG15 and the epsilon-amino group of lysine residues in the substrate.
E3