Cargando…

ISG15 deficiency and increased viral resistance in humans but not mice

ISG15 is an interferon (IFN)-α/β-induced ubiquitin-like protein. It exists as a free molecule, intracellularly and extracellularly, and conjugated to target proteins. Studies in mice have demonstrated a role for Isg15 in antiviral immunity. By contrast, human ISG15 was shown to have critical immune...

Descripción completa

Detalles Bibliográficos
Autores principales: Speer, Scott D., Li, Zhi, Buta, Sofija, Payelle-Brogard, Béatrice, Qian, Li, Vigant, Frederic, Rubino, Erminia, Gardner, Thomas J., Wedeking, Tim, Hermann, Mark, Duehr, James, Sanal, Ozden, Tezcan, Ilhan, Mansouri, Nahal, Tabarsi, Payam, Mansouri, Davood, Francois-Newton, Véronique, Daussy, Coralie F., Rodriguez, Marisela R., Lenschow, Deborah J., Freiberg, Alexander N., Tortorella, Domenico, Piehler, Jacob, Lee, Benhur, García-Sastre, Adolfo, Pellegrini, Sandra, Bogunovic, Dusan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4873964/
https://www.ncbi.nlm.nih.gov/pubmed/27193971
http://dx.doi.org/10.1038/ncomms11496
Descripción
Sumario:ISG15 is an interferon (IFN)-α/β-induced ubiquitin-like protein. It exists as a free molecule, intracellularly and extracellularly, and conjugated to target proteins. Studies in mice have demonstrated a role for Isg15 in antiviral immunity. By contrast, human ISG15 was shown to have critical immune functions, but not in antiviral immunity. Namely, free extracellular ISG15 is crucial in IFN-γ-dependent antimycobacterial immunity, while free intracellular ISG15 is crucial for USP18-mediated downregulation of IFN-α/β signalling. Here we describe ISG15-deficient patients who display no enhanced susceptibility to viruses in vivo, in stark contrast to Isg15-deficient mice. Furthermore, fibroblasts derived from ISG15-deficient patients display enhanced antiviral protection, and expression of ISG15 attenuates viral resistance to WT control levels. The species-specific gain-of-function in antiviral immunity observed in ISG15 deficiency is explained by the requirement of ISG15 to sustain USP18 levels in humans, a mechanism not operating in mice.