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

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.

• Authors: 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 Wang, Hui 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
• Journal: Nature (Nature) Vol. 517 Issue 7532 Pg. 89-93 (Jan 01 2015) ISSN: 1476-4687 [Electronic] England
• PMID: 25307056 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Interferon Type I
• S-Phase Kinase-Associated Proteins
• Ubiquitins
• ISG15 protein, human
• Endopeptidases
• USP18 protein, human
• Ubiquitin Thiolesterase

Topics

• Adolescent
• Alleles
• Child
• Cytokines (deficiency, genetics, metabolism)
• Endopeptidases (chemistry, metabolism)
• Female
• Gene Expression Regulation
• Humans
• Inflammation (genetics, immunology, prevention & control)
• Interferon Type I (immunology, metabolism)
• Intracellular Space (metabolism)
• Male
• Pedigree
• S-Phase Kinase-Associated Proteins (metabolism)
• Signal Transduction
• Ubiquitin Thiolesterase
• Ubiquitination
• Ubiquitins (deficiency, genetics, metabolism)
• Viruses (immunology)