ISG15 has been challenging to study due to its absence in genetically tractable model organisms such as yeast, its multiple modes of action (as a cytokine, covalent modification and non-covalent interaction), its absence prior to induction following infection and its C-terminal LRLRGG motif, which is indistinguishable from that of ubiquitin or NEDD8. The gene discussed is NEDD8; the disease is infection.