ISG15 (Interferon Stimulated Gene, 15kDa) is a ubiquitin-like modifier which initiates innate immune response by activating RIG-I signaling, stimulating NK-cell proliferation, inhibiting viral budding and acting as an IFNγ-inducing cytokine. ISG15 contains two tandem ubiquitin homology domains and is cross-reactive with α-Ubiquitin antibodies. Conjugation of ISG15 to a substrate protein occurs through a ubiquitin like cascade via an E1 (UBE1L), E2 (UbcH8/UBE2L6) and E3 (not yet discovered.) Deconjugation normally occurs via UBP43 (USP18), however there are several viral proteases that are able to hydrolyze ISG15 conjugates in order to evade immune response. These include the OTU-containing protease of Crimean-Congo Hemorrhagic Fever nairovirus and the Papain-Like Protease (PLPro) of the SARS coronavirus.