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ISG15 deficiency and increased viral resistance in humans but not mice

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 Tezc, 2016. "ISG15 deficiency and increased viral resistance in humans but not mice," Nature Communications, Nature, vol. 7(1), pages 1-10, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11496
    DOI: 10.1038/ncomms11496
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