ISG15 deficiency and increased viral resistance in humans but not mice

Scott D. Speer, Zhi Li, Sofija Buta, Béatrice Payelle-Brogard, Li Qian, Frederic Vigant, Erminia Rubino, Thomas J. Gardner, Tim Wedeking, Mark Hermann, James Duehr, Ozden Sanal, Ilhan Tezcan, Nahal Mansouri, Payam Tabarsi, Davood Mansouri, Véronique Francois-Newton, Coralie F. Daussy, Marisela R. Rodriguez, Deborah J. Lenschow, Alexander N. Freiberg, Domenico Tortorella, Jacob Piehler, Benhur Lee, Adolfo García-Sastre, Sandra Pellegrini () and Dusan Bogunovic ()
Additional contact information
Scott D. Speer: Icahn School of Medicine at Mount Sinai
Zhi Li: Institut Pasteur, Cytokine Signalling Unit
Sofija Buta: Icahn School of Medicine at Mount Sinai
Béatrice Payelle-Brogard: Institut Pasteur, Cytokine Signalling Unit
Li Qian: Icahn School of Medicine at Mount Sinai
Frederic Vigant: Icahn School of Medicine at Mount Sinai
Erminia Rubino: Institut Pasteur, Cytokine Signalling Unit
Thomas J. Gardner: Icahn School of Medicine at Mount Sinai
Tim Wedeking: University of Osnabrück
Mark Hermann: Icahn School of Medicine at Mount Sinai
James Duehr: Icahn School of Medicine at Mount Sinai
Ozden Sanal: Hacettepe University, Ihsan Dogramaci Children’s Hospital
Ilhan Tezcan: Hacettepe University, Ihsan Dogramaci Children’s Hospital
Nahal Mansouri: Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences
Payam Tabarsi: Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences
Davood Mansouri: Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences
Véronique Francois-Newton: Institut Pasteur, Cytokine Signalling Unit
Coralie F. Daussy: Institut Pasteur, Cytokine Signalling Unit
Marisela R. Rodriguez: Washington University School of Medicine
Deborah J. Lenschow: Washington University School of Medicine
Alexander N. Freiberg: University of Texas Medical Branch
Domenico Tortorella: Icahn School of Medicine at Mount Sinai
Jacob Piehler: University of Osnabrück
Benhur Lee: Icahn School of Medicine at Mount Sinai
Adolfo García-Sastre: Icahn School of Medicine at Mount Sinai
Sandra Pellegrini: Institut Pasteur, Cytokine Signalling Unit
Dusan Bogunovic: Icahn School of Medicine at Mount Sinai

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms11496

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