ISG15: In Sickness and in Health

ISG15 is a ubiquitin-like molecule induced by type I IFN. ISG15 can both be conjugated to other proteins and exist as a free protein. Soluble ISG15 can induce IFN-γ. Murine ISG15 appears to be largely antiviral, as often expected for ISGs, and knockout mice are more susceptible to several, although not all, viruses. However, humans deficient for ISG15 do not have an increased susceptibility to viral infections. ISG15 stabilizes ubiquitin-specific peptidase 18 (USP18) in humans and, thus, acts as a negative regulator of IFN signaling. Therefore, in humans in vivo, ISG15 appears to act primarily to dampen IFN-induced inflammation, explaining the lack of susceptibility observed in patients. ISG15 is a type I interferon (IFN)-inducible gene encoding a protein with pleiotropic functions, acting both as a soluble molecule and as a protein modifier. Surprisingly, and despite the antiviral functions of ISG15 described in mice, humans born with inactivating mutations of ISG15 do not present with any overt viral phenotype, but are highly susceptible to environmental mycobacteria and have autoinflammatory disease presentations. In vitro, ISG15 deficiency also leads to persistently high levels of type I IFN-stimulated gene expression and to increased resistance to all viruses tested to date. This suggests that ISG15 deficiency increases antiviral responses in humans, in stark contrast to expectations based on mouse experiments. We discuss here the roles of each of the forms of ISG15 in health and disease, as well as the differences between species. ISG15 is a type I interferon (IFN)-inducible gene encoding a protein with pleiotropic functions, acting both as a soluble molecule and as a protein modifier. Surprisingly, and despite the antiviral functions of ISG15 described in mice, humans born with inactivating mutations of ISG15 do not present with any overt viral phenotype, but are highly susceptible to environmental mycobacteria and have autoinflammatory disease presentations. In vitro, ISG15 deficiency also leads to persistently high levels of type I IFN-stimulated gene expression and to increased resistance to all viruses tested to date. This suggests that ISG15 deficiency increases antiviral responses in humans, in stark contrast to expectations based on mouse experiments. We discuss here the roles of each of the forms of ISG15 in health and disease, as well as the differences between species.