Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation (original) (raw)

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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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Acknowledgements

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.

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Author notes

1. These authors contributed equally to this work.
2. Jean-Laurent Casanova and Sandra Pellegrini: These authors jointly supervised this work.
3. Xianqin Zhang, Dusan Bogunovic, Béatrice Payelle-Brogard and Véronique Francois-Newton: These authors contributed equally to this work.
4. Jean-Laurent Casanova and Sandra Pellegrini: These authors jointly supervised this work.

Authors and Affiliations

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, 10065, New York, 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, 10029, New York, 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, 10029, New York, 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, 10029, New York, USA
   Scott D. Speer
7. Division of Immunology, Children’s Hospital Boston, Boston, 02115, Massachusetts, 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. Department of Molecular Cardiology, Center for Cardiovascular Genetics, 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, 10029, New York, 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, 10065, New York , USA
    Jean-Laurent Casanova
27. Pediatric Hematology–Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France ,
    Jean-Laurent Casanova

Authors

1. Xianqin Zhang
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2. Dusan Bogunovic
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3. Béatrice Payelle-Brogard
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4. Véronique Francois-Newton
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5. Scott D. Speer
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6. Chao Yuan
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7. Stefano Volpi
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8. Zhi Li
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9. Ozden Sanal
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10. Davood Mansouri
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11. Ilhan Tezcan
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12. Gillian I. Rice
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13. Chunyuan Chen
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14. Nahal Mansouri
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15. Seyed Alireza Mahdaviani
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16. Yuval Itan
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17. Bertrand Boisson
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18. Satoshi Okada
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19. Lu Zeng
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20. Xing Wang
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21. Hui Jiang
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22. Wenqiang Liu
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23. Tiantian Han
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24. Delin Liu
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25. Tao Ma
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26. Bo Wang
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27. Mugen Liu
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28. Jing-Yu Liu
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29. Qing K. Wang
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30. Dilek Yalnizoglu
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31. Lilliana Radoshevich
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32. Gilles Uzé
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33. Philippe Gros
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34. Flore Rozenberg
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35. Shen-Ying Zhang
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36. Emmanuelle Jouanguy
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37. Jacinta Bustamante
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38. Adolfo García-Sastre
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39. Laurent Abel
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40. Pierre Lebon
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41. Luigi D. Notarangelo
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42. Yanick J. Crow
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43. Stéphanie Boisson-Dupuis
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44. Jean-Laurent Casanova
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45. Sandra Pellegrini
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Contributions

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.

Corresponding author

Correspondence toDusan Bogunovic.

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The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Mutations in ISG15-deficient individuals, allele characterization and serum IFN-α concentrations.

a, Sanger sequencing of ISG15 exon 2 from genomic DNA in kindred C, with the variants highlighted. b, The wild type (WT) and three mutant alleles (G55X, L114fs, E127X- ISG15) were inserted into an expression vector and used to transfect HEK293T cells. Other HEK293T cells were mock-transfected (mock) or left untransfected (not transf.). The cell lysates isolated were subjected to western blotting, with recombinant human (Rh)-ISG15 used as a control. c, d, Plasma samples from P1, P2, P3, P5, P6 and the mother and brother of P5/6 were used in cytopathic protection assays, to measure antiviral activity (c) and blocking antibodies against IFN-α were used to assess specificity (d) (experiment was performed one time).

Extended Data Figure 2 A form of ISG15 that cannot be conjugated rescues the phenotype of ISG15-deficient cells.

a, Lentiviral particles containing luciferase, wild-type (WT) ISG15-RFP or ISG15(ΔGG)-RFP genes were used to transduce hTert-immortalized fibroblasts from C1, a STAT1−/− subject, P1, P2 and P3. RFP-positive cells were obtained by sorting and were cultured for a few weeks. The cells were then treated with 1,000 IU of IFN-α2b for 12 h, washed with PBS and left to rest for 36 h, after which relative mRNA levels for IFIT1 were determined. b, The experimental setting described in a was used in the presence or absence of vehicle control, anti-ISG15 antibodies or control IgG for luciferase and wild-type ISG15–RFP-transduced C1 and P1 hTert-immortalized fibroblasts (showing representative experiments with technical replicates and s.e.m., out of 3 performed).

Extended Data Figure 3 Prolonged IFN signalling, low USP18, and high interferon-stimulated-gene-encoded protein levels in patient-derived cells and in ISG15-silenced human fibrosarcoma HLLR1-1.4 cells.

a, Left panels, SV40-immortalized fibroblasts from two controls (C10 and C12) and two ISG15-deficient patients (P1 and P2) were stimulated with IFN-β (500 pM) for 4 to 36 h. Cell lysates (30 µg) were analysed with the indicated antibodies. Right, EBV-transformed B cells from control (C3) and patient P1 were stimulated with IFN-β for 8 to 24 h. Cell lysates (30 µg) were analysed with the indicated antibodies. b, HLLR1-1.4 cells were transfected with control siRNA or ISG15 siRNA. One day post-transfection, IFN-β (500 pM) was added for various amounts of time. Cell lysates (30 µg) were analysed with the indicated antibodies (MxA and MX1 are used synonymously). c, WISH cells were stimulated and lysates analysed as described in b. d, HLLR1-1.4 cells were transfected with control siRNA, USP18 siRNA and UbcH8 (also known as UBE2E2) siRNA (left) or control siRNA, USP18 siRNA and HERC5 siRNA (right). One day post-transfection, cells were left untreated (naive) or were primed for 8 h with IFN-β (500 pM). Cells were washed and left to rest for 16 h before being pulsed for 30 min with 100 pM IFN-α2 or IFN-β. Cell lysates (30 µg) were analysed with the indicated antibodies.

Extended Data Figure 4 ISG15 controls the stability of the USP18 protein, but not of other interferon-stimulated-gene products.

a, HLLR1-1.4 cells were transfected with either control siRNA or ISG15 siRNA. One day post-transfection, cells were stimulated with IFN-β (500 pM) for 6 h. Cycloheximide (CHX, 20 µg ml−1) was then added for various time periods, from 30 min to 5 h. Cell lysates (30 µg) were analysed with the indicated antibodies. b, As in a, with additional controls, cells treated with IFN only. Several interferon-stimulated genes were analysed. c, hTert-immortalized fibroblasts from patient P1 transduced with lentiviral particles expressing RFP and luciferase and wild-type ISG15 (LV ISG15 WT) were stimulated with IFN-β (500 pM) for 6 h. CHX was then added for the indicated times. Cell lysates (15 µg) were analysed by western blotting. d, HEK293T cells were transfected with USP18, HA–ubiquitin and Flag–ISG15 as indicated. Two days later, cells were lysed in modified RIPA buffer, USP18 was immunoprecipitated (IP) and analysed with anti-USP18 antibodies. Left panels, cell lysates (30 µg) were analysed by western blot with the indicated antibodies. Right panels, the immunoprecipitates were gel separated and transferred onto a membrane. The membrane was cut into two parts above the 50 kDa marker, both of which were blotted with anti-USP18 antibodies. The top part was exposed for 2 min, the bottom part for 20 s. Asterisk indicates IgG heavy chain. e, HEK293T cells were transfected with 1 µg of the USP18 construct alone or with 1 µg of HA–ubiquitin, in the presence or absence of Flag-tagged ISG15, either wild type or a mutant form of ISG15 that cannot be conjugated as it lacks the two carboxy-terminal glycine residues (Flag–ISG15(ΔGG)). Two days later, cells were lysed in modified RIPA buffer, USP18 was immunoprecipitated and analysed with anti-HA or anti-USP18 antibodies. Asterisk indicates IgG heavy chain. f, hTert-immortalized fibroblasts from patient P3 were transfected with control siRNA or SKP2 siRNA. We added IFN-β (500 pM) 24 h later and the cells were incubated for the indicated times. Cell lysates were analysed with the indicated antibodies and USP18 levels were determined as a function of actin levels.

Extended Data Figure 5 Autoantibody development in ISG15-deficient individuals.

a, b, Serum samples from ISG15-deficient, SLE and AGS patients were evaluated for the presence of IgG and IgA autoantibodies in a blinded experiment. Values for the negative control samples for each antigen were averaged and ratios of each sample to the mean for the negative controls plus 2 standard deviations were calculated, with values greater than 1 considered positive. A heat map of the ratio values was generated with MultiExperiment Viewer software (MeV, DFCI Boston, MA), with values coded as follows: 0, blue; 1, black; 5, yellow.

Extended Data Table 1 Patients have normal titres of antibodies against many viral antigens

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Extended Data Table 2 Whole-exome sequencing results for patients with putative IBGC

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Extended Data Table 3 Homozygous variants of genes other than ISG15 present in P1, P2, P5 and P6

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Extended Data Table 4 ISG15-deficient hTert fibroblasts have enhanced responses to IFN-α

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Zhang, X., Bogunovic, D., Payelle-Brogard, B. et al. Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation.Nature 517, 89–93 (2015). https://doi.org/10.1038/nature13801

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• Received: 01 December 2013
• Accepted: 27 August 2014
• Published: 12 October 2014
• Issue Date: 01 January 2015
• DOI: https://doi.org/10.1038/nature13801