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

Xianqin Zhang, Dusan Bogunovic, Béatrice Payelle-Brogard, Véronique Francois-Newton, Scott D. Speer, Chao Yuan, Stefano Volpi, Zhi Li, Ozden Sanal, Davood Mansouri, Ilhan Tezcan, Gillian I. Rice, Chunyuan Chen, Nahal Mansouri, Seyed Alireza Mahdaviani, Yuval Itan, Bertrand Boisson, Satoshi Okada, Lu Zeng, Xing WangHui Jiang, Wenqiang Liu, Tiantian Han, Delin Liu, Tao Ma, Bo Wang, Mugen Liu, Jing Yu Liu, Qing K. Wang, Dilek Yalnizoglu, Lilliana Radoshevich, Gilles Uzé, Philippe Gros, Flore Rozenberg, Shen Ying Zhang, Emmanuelle Jouanguy, Jacinta Bustamante, Adolfo García-Sastre, Laurent Abel, Pierre Lebon, Luigi D. Notarangelo, Yanick J. Crow, Stéphanie Boisson-Dupuis, Jean Laurent Casanova, Sandra Pellegrini

Research output: Contribution to journalArticlepeer-review

425 Scopus citations

Abstract

Intracellular ISG15 is an interferon (IFN)-α/β-inducible ubiquitinlike 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 ISG15deficiency 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 displayunanticipated cellular, immunological and clinical signs of enhanced IFN-α/β immunity, reminiscent of the Mendelian autoinflammatory interferonopathiesAicardi-Goutieres syndrome andspondyloenchondrodysplasia.We further showthat 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 IFNα/β responses. Human ISG15, therefore, is not only redundant for antiviral immunity, but is a key negative regulator of IFN-α/β immunity. Inhumans, 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.

Original languageEnglish
Pages (from-to)89-93
Number of pages5
JournalNature
Volume517
Issue number7532
DOIs
StatePublished - 1 Jan 2015

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