Journal Article

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

García-Sastre, Adolfo, Liu, Delin, Interactions Bactéries-Cellules (UIBC) ; Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lebon, Pierre, Università degli Studi di Brescia = University of Brescia (UniBs), Okada, Satoshi, Wang, Qing, Génétique Humaine des Maladies Infectieuses (Inserm U980) ; Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hunan Institute of Science and Technology, Rice, Gillian, Bogunovic, Bo, Zeng, Lu, Yuan, Chao, St. Giles Laboratory of Human Genetics of Infectious Diseases ; Rockefeller University [New York], Department of Mathematics [Nanjing] ; Nanjing University of Aeronautics and Astronautics [Nanjing] (NUAA), Sanal, Ozden, Huazhong University of Science and Technology [Wuhan] (HUST), Ma, Tao, Boisson, Bertrand, Liu, Wenqiang, Liu, Jing-Yu, Shahid Beheshti University of Medical Sciences [Tehran] (SBUMS), Imagine - Institut des maladies géné

2015

Overview

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.

• Publisher: Nature Publishing Group,CCSD,Nature Publishing Group UK
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