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; Dusan Bogunovic

doi:10.1038/ncomms11496

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. LenschowAlexander N. Freiberg, Domenico Tortorella, Jacob Piehler, Benhur Lee, Adolfo García-Sastre, Sandra Pellegrini, Dusan Bogunovic

Research output: Contribution to journal › Article › peer-review

80 Scopus citations

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-I 3-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.

Original language	English (US)
Article number	11496
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms11496
State	Published - May 19 2016
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General
General Physics and Astronomy

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Speer, S. D., Li, Z., Buta, S., Payelle-Brogard, B., Qian, L., Vigant, F., Rubino, E., Gardner, T. J., Wedeking, T., Hermann, M., Duehr, J., Sanal, O., Tezcan, I., Mansouri, N., Tabarsi, P., Mansouri, D., Francois-Newton, V., Daussy, C. F., Rodriguez, M. R., ... Bogunovic, D. (2016). ISG15 deficiency and increased viral resistance in humans but not mice. Nature communications, 7, Article 11496. https://doi.org/10.1038/ncomms11496

Speer, SD, Li, Z, Buta, S, Payelle-Brogard, B, Qian, L, Vigant, F, Rubino, E, Gardner, TJ, Wedeking, T, Hermann, M, Duehr, J, Sanal, O, Tezcan, I, Mansouri, N, Tabarsi, P, Mansouri, D, Francois-Newton, V, Daussy, CF, Rodriguez, MR, Lenschow, DJ, Freiberg, AN, Tortorella, D, Piehler, J, Lee, B, García-Sastre, A, Pellegrini, S & Bogunovic, D 2016, 'ISG15 deficiency and increased viral resistance in humans but not mice', Nature communications, vol. 7, 11496. https://doi.org/10.1038/ncomms11496

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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-I 3-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.",

author = "Speer, {Scott D.} and Zhi Li and Sofija Buta and B{\'e}atrice Payelle-Brogard and Li Qian and Frederic Vigant and Erminia Rubino and Gardner, {Thomas J.} and Tim Wedeking and Mark Hermann and James Duehr and Ozden Sanal and Ilhan Tezcan and Nahal Mansouri and Payam Tabarsi and Davood Mansouri and V{\'e}ronique Francois-Newton and Daussy, {Coralie F.} and Rodriguez, {Marisela R.} and Lenschow, {Deborah J.} and Freiberg, {Alexander N.} and Domenico Tortorella and Jacob Piehler and Benhur Lee and Adolfo Garc{\'i}a-Sastre and Sandra Pellegrini and Dusan Bogunovic",

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AU - Speer, Scott D.

AU - Li, Zhi

AU - Buta, Sofija

AU - Payelle-Brogard, Béatrice

AU - Qian, Li

AU - Vigant, Frederic

AU - Rubino, Erminia

AU - Gardner, Thomas J.

AU - Wedeking, Tim

AU - Hermann, Mark

AU - Duehr, James

AU - Sanal, Ozden

AU - Tezcan, Ilhan

AU - Mansouri, Nahal

AU - Tabarsi, Payam

AU - Mansouri, Davood

AU - Francois-Newton, Véronique

AU - Daussy, Coralie F.

AU - Rodriguez, Marisela R.

AU - Lenschow, Deborah J.

AU - Freiberg, Alexander N.

AU - Tortorella, Domenico

AU - Piehler, Jacob

AU - Lee, Benhur

AU - García-Sastre, Adolfo

AU - Pellegrini, Sandra

AU - Bogunovic, Dusan

PY - 2016/5/19

Y1 - 2016/5/19

N2 - 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-I 3-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.

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ISG15 deficiency and increased viral resistance in humans but not mice

Abstract

ASJC Scopus subject areas

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