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Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation

Xianqin Zhang 1 Bo Bogunovic Béatrice Payelle-Brogard 2 Véronique François-Newton 2 Scott Speer Chao Yuan Stefano Volpi 3 Zhi Li 2 Ozden Sanal 4 Ilhan Tezcan 4 Gillian Rice 5 Chunyuan Chen Nahal Mansouri 6 Seyed Alireza Mahdaviani 7 Yuval Itan 8 Bertrand Boisson 9 Satoshi Okada 8 Lu Zeng Xing Wang Hui Jiang 10 Wenqiang Liu Tiantian Han Delin Liu Tao Ma Bo Wang 11 Mugen Liu 1 Jing-Yu Liu Qing Wang 12 Dilek Yalnizoglu Lilliana Radoshevich 13 Gilles Uze 14 Philippe Gros 15 Flore Rozenberg 16 Shen-Ying Zhang 8 Emmanuelle Jouanguy 17 Jacinta Bustamante 18 Adolfo García-Sastre 19 Laurent Abel 17 Pierre Lebon 20 Luigi Notarangelo 21 Yanick Crow 18 Stephanie Boisson-Dupuis 18 Jean-Laurent Casanova 17 Sandra Pellegrini 2
1 HUST - Huazhong University of Science and Technology [Wuhan]
2 Signalisation des Cytokines
3 Istituto Giannina Gaslini, Genova
4 Ankara University School of Medicine [Turkey]
5 University of Manchester [Manchester]
6 SBUMS - Shahid Beheshti University of Medical Sciences [Tehran]
7 Shahid Beheshti University
8 St. Giles Laboratory of Human Genetics of Infectious Diseases
9 ISV - Institut des sciences du végétal
10 Nanjing University of Aeronautics and Astronautics - Department of Mathematics
11 IRCOM - Institut de Recherche en Communications Optiques et Microondes
12 Hunan Institute of Science and Technology
13 UIBC - Interactions Bactéries-Cellules
14 DIMNP - Dynamique des interactions membranaires normales et pathologiques
15 DPP - Département de Physique des Particules (ex SPP)
16 Laboratoire de Virologie
17 Inserm U980 - Génétique Humaine des Maladies Infectieuses
18 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
19 MSSM - Icahn School of Medicine at Mount Sinai [New York]
20 Service de virologie
21 Department of Pediatrics and Institute for Molecular Medicine Angello Nocivelli
Abstract : Intracellular ISG15 is an interferon (IFN)-α/β-inducible ubiquitin-like modifier which can covalently bind other proteins in a process called ISGylation; it is an effector of IFN-α/β-dependent antiviral immunity in mice. We previously published a study describing humans with inherited ISG15 deficiency but without unusually severe viral diseases. We showed that these patients were prone to mycobacterial disease and that human ISG15 was non-redundant as an extracellular IFN-γ-inducing molecule. We show here that ISG15-deficient patients also display unanticipated cellular, immunological and clinical signs of enhanced IFN-α/β immunity, reminiscent of the Mendelian autoinflammatory interferonopathies Aicardi-Goutières syndrome and spondyloenchondrodysplasia. We further show that an absence of intracellular ISG15 in the patients' cells prevents the accumulation of USP18, a potent negative regulator of IFN-α/β signalling, resulting in the enhancement and amplification of IFN-α/β responses. Human ISG15, therefore, is not only redundant for antiviral immunity, but is a key negative regulator of IFN-α/β immunity. In humans, intracellular ISG15 is IFN-α/β-inducible not to serve as a substrate for ISGylation-dependent antiviral immunity, but to ensure USP18-dependent regulation of IFN-α/β and prevention of IFN-α/β-dependent autoinflammation.
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https://hal-pasteur.archives-ouvertes.fr/pasteur-02070691
Contributor : Zhi Li <>
Submitted on : Monday, March 18, 2019 - 11:05:30 AM
Last modification on : Wednesday, August 19, 2020 - 11:17:51 AM

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PASTEUR | CNRS | INRA | UNILIM | CEA | CEA-UPSAY | DSM-IRFU | UNIV-PARIS5 | BS | UNIV-MONTPELLIER | I2BC | CEA-DRF | USPC | UNIV-PARIS-SACLAY | JOLIOT | INRAE | UNIV-PARIS | UP-SANTE

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Xianqin Zhang, Bo Bogunovic, Béatrice Payelle-Brogard, Véronique François-Newton, Scott Speer, et al.. Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation. Nature, Nature Publishing Group, 2015, 517 (7532), pp.89-93. ⟨10.1038/nature13801⟩. ⟨pasteur-02070691⟩

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