Human intracellular ISG15 prevents interferon-[alpha]/[Beta] over-amplification and auto-inflammation

• Published in: Nature (London) Vol. 517; no. 7532; p. 89
• Main Authors: Zhang, Xianqin, Bogunovic, Dusan, Payelle-Brogard, Béatrice, Francois-Newton, Véronique, Speer, Scott D, Yuan, Chao, Volpi, Stefano, Li, Zhi, Sanal, Ozden, Mansouri, Davood, Tezcan, Ilhan, Rice, Gillian I, Chen, Chunyuan, Mansouri, Nahal, Mahdaviani, Seyed Alireza, Itan, Yuval, Boisson, Bertrand, Okada, Satoshi, Zeng, Lu, Wang, Xing, Jiang, Hui, Liu, Wenqiang, Han, Tiantian, Liu, Delin, Ma, Tao, Wang, Bo, Liu, Mugen, Liu, Jing-Yu, Wang, Qing K, Yalnizoglu, Dilek, Radoshevich, Lilliana, Uzé, Gilles, Gros, Philippe, Rozenberg, Flore, Zhang, Shen-Ying, Jouanguy, Emmanuelle, Bustamante, Jacinta, García-Sastre, Adolfo, Abel, Laurent, Lebon, Pierre, Notarangelo, Luigi D, Crow, Yanick J, Boisson-Dupuis, Stéphanie, Casanova, Jean-Laurent, Pellegrini, Sandra
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01.01.2015
• Subjects: Calcification; Disease; Infections; Interferon; Mutation; Proteins; Viral infections
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature13801

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 mice1-4. We previously published a study describing humans with inherited ISG15 deficiency but without unusually severe viral diseases5. We showed that these patients were prone to myco-bacterial 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 interferonopathiesAicardi-Goutières syndrome and spondyloenchondrodysplasia6-9.We further show that an absence of intracellular ISG15 in the patients' cells prevents the accumulation of USP1810,11, 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. 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.