• An Erratum to this article was published on 11 February 2015


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 mice1,2,3,4. 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 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 spondyloenchondrodysplasia6,7,8,9. 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. 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.

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Data deposits

Microarray data have been deposited in the Gene Expression Omnibus under accession number GSE60359; WES data have been deposited in the BioProject database under accession number PRJNA167660.


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The Laboratory of Human Genetics of Infectious Diseases is supported by grants from the French National Agency for Research (ANR), the EU grant HOMITB (HEALTH-F32008-200732), the St Giles Foundation, the National Center for Research Resources and the National Center for Advancing Sciences (NCATS), National Institutes of Health grant number 8UL1TR000043, the Rockefeller University, the National Institute of Allergy and Infectious Diseases grant number R37AI095983, Institut Merieux research grant and the Empire State Stem Cell fund through NYSDOH Contract #C023046 to Flow Cytometry Research Core at the Rockefeller University. The Cytokine Signaling Unit is supported by the Institut Pasteur, CNRS and INSERM. S.P. and G.U. received funding from the EU Seventh Framework Programme under grant agreement 223608. V.F.-N. was supported by the Ligue contre le Cancer. L.R. is a Human Frontier Science Program long-term fellow. L.D.N. was supported by the National Institute of Allergy and Infectious Diseases grant number 1PO1AI076210-01A1. Y.J.C. thanks the Manchester Biomedical Research Centre and the Greater Manchester Comprehensive Local Research Network, the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement 241779, and the European Research Council (GA 309449). A.G.-S. acknowledges NIAID grants U19AI083025 and P01AI090935 for support. We thank C. Daussy for technical assistance, E. Bianchi and F. Michel for discussions. We thank D. Zhang and the members of the Zhang laboratory for assistance, advice and discussions. This work was supported by Chinese National Natural Science Foundation grants (81000079, 81170165) to X.Z. D.B. is supported by the National Institute of Allergy and Infectious Diseases grant number R00AI106942-02.

Author information

Author notes

    • Jean-Laurent Casanova
    •  & Sandra Pellegrini

    These authors jointly supervised this work.

    • Xianqin Zhang
    • , Dusan Bogunovic
    • , Béatrice Payelle-Brogard
    •  & Véronique Francois-Newton

    These authors contributed equally to this work.

    • Jean-Laurent Casanova
    •  & Sandra Pellegrini

    These authors jointly supervised this work.


  1. Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China

    • Xianqin Zhang
    • , Chao Yuan
    • , Lu Zeng
    • , Xing Wang
    • , Wenqiang Liu
    • , Tiantian Han
    • , Tao Ma
    • , Mugen Liu
    • , Jing-Yu Liu
    •  & Qing K. Wang
  2. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York 10065, USA

    • Dusan Bogunovic
    • , Yuval Itan
    • , Bertrand Boisson
    • , Satoshi Okada
    • , Shen-Ying Zhang
    • , Laurent Abel
    • , Stéphanie Boisson-Dupuis
    •  & Jean-Laurent Casanova
  3. Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA

    • Dusan Bogunovic
    • , Scott D. Speer
    •  & Adolfo García-Sastre
  4. Institut Pasteur, Cytokine Signaling Unit, CNRS URA 1961, 75724 Paris, France

    • Béatrice Payelle-Brogard
    • , Véronique Francois-Newton
    • , Zhi Li
    •  & Sandra Pellegrini
  5. Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA

    • Scott D. Speer
    •  & Adolfo García-Sastre
  6. Microbiology Training Area, Graduate School of Biomedical Sciences of Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA

    • Scott D. Speer
  7. Division of Immunology, Children’s Hospital Boston, Boston, Massachusetts 02115, USA

    • Stefano Volpi
    •  & Luigi D. Notarangelo
  8. Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16132 Genoa, Italy

    • Stefano Volpi
  9. Immunology Division and Pediatric Neurology Department, Hacettepe University Children’s Hospital, 06100 Ankara, Turkey

    • Ozden Sanal
    • , Ilhan Tezcan
    •  & Dilek Yalnizoglu
  10. Division of Infectious Diseases and Clinical Immunology, Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, 4739 Teheran, Iran

    • Davood Mansouri
    • , Nahal Mansouri
    •  & Seyed Alireza Mahdaviani
  11. Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, M13 9NT, UK

    • Gillian I. Rice
    •  & Yanick J. Crow
  12. Department of Pediatrics, Third Xiangya Hospital, Central South University, Changsha 410013, China

    • Chunyuan Chen
  13. BGI-Shenzhen, Shenzhen 518083, China

    • Hui Jiang
  14. Sangzhi County People's Hospital, Sangzhi 427100, China

    • Delin Liu
  15. Genetics Laboratory, Hubei Maternal and Child Health Hospital, Wuhan, Hubei 430070, China

    • Bo Wang
  16. Center for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA

    • Qing K. Wang
  17. Institut Pasteur, Bacteria-Cell Interactions Unit, 75724 Paris, France

    • Lilliana Radoshevich
  18. CNRS UMR5235, Montpellier II University, Place Eugène Bataillon, 34095 Montpellier, France

    • Gilles Uzé
  19. Department of Biochemistry, McGill University, Montreal, QC H3A 0G4, Canada

    • Philippe Gros
  20. Paris Descartes University, 75006 Paris, France

    • Flore Rozenberg
    •  & Pierre Lebon
  21. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France

    • Emmanuelle Jouanguy
    • , Jacinta Bustamante
    • , Laurent Abel
    • , Stéphanie Boisson-Dupuis
    •  & Jean-Laurent Casanova
  22. Paris Descartes University, Imagine Institute, 75015 Paris, France

    • Emmanuelle Jouanguy
    • , Jacinta Bustamante
    • , Laurent Abel
    • , Yanick J. Crow
    • , Stéphanie Boisson-Dupuis
    •  & Jean-Laurent Casanova
  23. Center for the Study of Primary Immunodeficiencies, Necker Hospital for Sick Children, 75015 Paris, France

    • Jacinta Bustamante
  24. Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA

    • Adolfo García-Sastre
  25. INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Imagine Institute, 75006 Paris, France

    • Yanick J. Crow
  26. Howard Hughes Medical Institute, New York, New York 10065, USA

    • Jean-Laurent Casanova
  27. Pediatric Hematology–Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France

    • Jean-Laurent Casanova


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D.B., X.Z., B.P.-B., V.F.-N., O.S., D.M., P.G., A.G.-S., L.A., P.L., L.D.N., S.B.-D., Y.J.C., J.-L.C. and S.P. wrote the manuscript. D.B., X.Z., B.P.-B., V.F.-N., S.D.S., C.Y., S.V., Z.L., I.T., G.I.R., C.C., N.M., S.A.M., Y.I., B.B., S.O., L.Z., X.W., H.J., W.L., T.H., D.L., T.M., B.W., D.Y., L.R., G.U., P.G., F.R., S.-Y.Z., E.J., J.B., A.G.-S., L.A., P.L., L.D.N., S.B.-D., Y.J.C., J.-L.C. and S.P. designed and/or performed experiments. M.L., J.-Y.L., Q.K.W., O.S., D.M., N.M., I.T. and S.A.M. took clinical care of the patients and provided advice.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Dusan Bogunovic.

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