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 10 Lu Zeng Xing Wang Hui Jiang 11 Wenqiang Liu Tiantian Han Delin Liu Tao Ma Bo Wang 12 Mugen Liu 1 Jing-Yu Liu Qing Wang 13 Dilek Yalnizoglu Lilliana Radoshevich 14 Gilles Uze 15 Philippe Gros 16 Flore Rozenberg 17 Shen-Ying Zhang 8 Emmanuelle Jouanguy 18 Jacinta Bustamante 19 Adolfo García-Sastre 20 Laurent Abel 18 Pierre Lebon 21 Luigi Notarangelo 22 Yanick Crow 19 Stephanie Boisson-Dupuis 19 Jean-Laurent Casanova 18 Sandra Pellegrini 2
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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Submitted on : Monday, March 18, 2019 - 11:05:30 AM
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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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