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ISG15 deficiency and increased viral resistance in humans but not mice.

Scott Speer 1 Zhi Li 2 Sofija Buta 1 Béatrice Payelle-Brogard 2 Li Qian 1 Frédéric Vigant 1 Erminia Rubino 2 Thomas Gardner 1 Tim Wedeking 3 Mark Hermann 1 James Duehr 1 Ozden Sanal 4 Ilhan Tezcan 4 Nahal Mansouri 5 Payam Tabarsi 5 Davood Mansouri 5 Véronique Francois-Newton 2 Coralie Daussy 2 Marisela Rodriguez 6 Deborah Lenschow 6 Alexander Freiberg 7 Domenico Tortorella 1 Jacob Piehler 3 Benhur Lee 1 Adolfo García-Sastre 1 Sandra Pellegrini 2, * Dusan Bogunovic 1, *
* Corresponding author
1 MSSM - Icahn School of Medicine at Mount Sinai [New York]
2 Signalisation des Cytokines
3 Osnabrück University
4 Hacettepe University = Hacettepe Üniversitesi
5 SBUMS - Shahid Beheshti University of Medical Sciences [Tehran]
6 University of Washington School of Medicine
7 UTMB - The University of Texas Medical Branch
Abstract : 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.
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Scott Speer, Zhi Li, Sofija Buta, Béatrice Payelle-Brogard, Li Qian, et al.. ISG15 deficiency and increased viral resistance in humans but not mice.. Nature Communications, Nature Publishing Group, 2016, 7, pp.11496. ⟨10.1038/ncomms11496⟩. ⟨pasteur-02070604⟩

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