Implications of myotis davidii interferon stimulated gene product 15 (iSG15) structure on iSG15 species-species diversity

Unlike ubiquitin (Ub) that is almost perfectly conserved among eukaryotes, Ub-like interferon-stimulated gene product 15 (ISG15) is highly divergent. Previously, structural studies on ISG15 have largely focused on human ISG15 and relied on the assumption that the structure of ISG15 between species would be analogous. In order to investigate the influence of species-species variance on the ISG15 structure fold, X-ray crystallography was used to obtain the full-length ISG15 structure from M. davidii. This structure illustrates that diversity goes beyond simple surface replacement and results in both secondary and tertiary differences. Viral proteases that seek to engage ISG15 to stymie host immune response are also shown to be sensitive to ISG15s species-species variations. Specifically, viral deISGylases appear to prefer ISG15s from species they productively infect. Put together, this conceivably represents not only an evolutionary pressure on viruses to adapt, but also may be an underlying driver of ISG15 sequence diversity.