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

1 HUST - Huazhong University of Science and Technology [Wuhan]
2 Signalisation des Cytokines
3 Istituto Giannina Gaslini, Genova
4 Ankara University School of Medicine [Turkey]
5 University of Manchester [Manchester]
6 SBUMS - Shahid Beheshti University of Medical Sciences [Tehran]
7 Shahid Beheshti University
8 St. Giles Laboratory of Human Genetics of Infectious Diseases
9 ISV - Institut des sciences du végétal
10 Department of Mathematics [Nanjing]
11 IRCOM - Institut de Recherche en Communications Optiques et Microondes
12 Hunan Institute of Science and Technology
13 UIBC - Interactions Bactéries-Cellules
14 DIMNP - Dynamique des interactions membranaires normales et pathologiques
15 DPhP - Département de Physique des Particules (ex SPP)
16 Laboratoire de Virologie
17 Inserm U980 - Génétique Humaine des Maladies Infectieuses
18 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
19 MSSM - Icahn School of Medicine at Mount Sinai [New York]
20 Service de virologie
21 UniBs - Università degli Studi di Brescia = University of Brescia

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.

Domains: Life Sciences [q-bio]; Genetics; Human genetics; Life Sciences [q-bio]; Immunology

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, 2015, 517 (7532), pp.89-93. ⟨10.1038/nature13801⟩. ⟨pasteur-02070691⟩