%0 Journal Article %T ISG15 deficiency and increased viral resistance in humans but not mice. %+ Icahn School of Medicine at Mount Sinai [New York] (MSSM) %+ Signalisation des Cytokines %+ Universität Osnabrück - Osnabrück University %+ Hacettepe University = Hacettepe Üniversitesi %+ Shahid Beheshti University of Medical Sciences [Tehran] (SBUMS) %+ University of Washington School of Medicine %+ The University of Texas Medical Branch (UTMB) %A Speer, Scott, D %A Li, Zhi %A Buta, Sofija %A Payelle-Brogard, Béatrice %A Qian, Li %A Vigant, Frédéric %A Rubino, Erminia %A Gardner, Thomas, J %A Wedeking, Tim %A Hermann, Mark %A Duehr, James %A Sanal, Ozden %A Tezcan, Ilhan %A Mansouri, Nahal %A Tabarsi, Payam %A Mansouri, Davood %A Francois-Newton, Véronique %A Daussy, Coralie, F %A Rodriguez, Marisela, R %A Lenschow, Deborah, J %A Freiberg, Alexander, N %A Tortorella, Domenico %A Piehler, Jacob %A Lee, Benhur %A García-Sastre, Adolfo %A Pellegrini, Sandra %A Bogunovic, Dusan %Z This was supported in part by NIH grant R00 AI106942-02 to D.B., NIH grant R01 AI101820 to D.T., an American Heart Association pre-doctoral fellowship and a USPHS Institutional Research Training Award T32-AI07647 to T.J.G., NRSA T32 AR07279-30 to M.R.R., NIH grant RO1 A1080672 and Pew Scholar Award to D.J.L., funding by the DFG (SFB 944) to J.P., NIH grant R33 AI102267 to A.N.F. and B.L., CRIP (Center for Research on Influenza Pathogenesis), and NIAID funded Center of Excellence for Influenza Research and Surveillance (contract #HHSN272201400008C) to AGS. Experimental support was provided by the Speed Congenics Facility of the Rheumatic Disease Core Center (P30 AR048335). Work in the Cytokine Signaling Unit was supported by Institut Pasteur, CNRS, INSERM and an Amgen Scholarship to E.R. %< avec comité de lecture %@ 2041-1723 %J Nature Communications %I Nature Publishing Group %V 7 %P 11496 %8 2016-12 %D 2016 %R 10.1038/ncomms11496 %M 27193971 %Z Life Sciences [q-bio]/Genetics %Z Life Sciences [q-bio]/ImmunologyJournal articles %X ISG15 is an interferon (IFN)-a/b-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-g-dependent antimycobacterial immunity, while free intracellular ISG15 is crucial for USP18-mediated downregulation of IFN-a/b 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. %G English %2 https://pasteur.hal.science/pasteur-02070604/document %2 https://pasteur.hal.science/pasteur-02070604/file/ncomms11496.pdf %L pasteur-02070604 %U https://pasteur.hal.science/pasteur-02070604 %~ PASTEUR %~ CNRS