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

Scott D Speer (1) , Zhi Li (2) , Sofija Buta (1) , Béatrice Payelle-Brogard (2) , Li Qian (1) , Frédéric Vigant (1) , Erminia Rubino (2) , Thomas J 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 F Daussy (2) , Marisela R Rodriguez (6) , Deborah J Lenschow (6) , Alexander N Freiberg (7) , Domenico Tortorella (1) , Jacob Piehler (3) , Benhur Lee (1) , Adolfo García-Sastre (1) , Sandra Pellegrini (2) , Dusan Bogunovic (1)

1 MSSM - Icahn School of Medicine at Mount Sinai [New York]
2 Signalisation des Cytokines
3 Universität Osnabrück - 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

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.

Domains: Genetics; Immunology

Scott D 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, 2016, 7, pp.11496. ⟨10.1038/ncomms11496⟩. ⟨pasteur-02070604⟩