Journal article
Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation
Nature (London), Vol.517(7532), pp.89-93
01/01/2015
DOI: 10.1038/nature13801
PMCID: PMC4303590
PMID: 25307056
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.
Details
- Title: Subtitle
- Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation
- Creators
- Xianqin Zhang - Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, ChinaDusan Bogunovic - 1] St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York 10065, USA Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USABéatrice Payelle-Brogard - Institut Pasteur, Cytokine Signaling Unit, CNRS URA 1961, 75724 Paris, FranceVéronique Francois-Newton - Institut Pasteur, Cytokine Signaling Unit, CNRS URA 1961, 75724 Paris, FranceScott D Speer - 1] Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA Microbiology Training Area, Graduate School of Biomedical Sciences of Icahn School of Medicine at Mount Sinai, New York, New York 10029, USAChao Yuan - Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, ChinaStefano Volpi - 1] Division of Immunology, Children's Hospital Boston, Boston, Massachusetts 02115, USA Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16132 Genoa, ItalyZhi Li - Institut PasteurOzden Sanal - Immunology Division and Pediatric Neurology Department, Hacettepe University Children's Hospital, 06100 Ankara, TurkeyDavood Mansouri - 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, IranIlhan Tezcan - Immunology Division and Pediatric Neurology Department, Hacettepe University Children's Hospital, 06100 Ankara, TurkeyGillian I Rice - Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, M13 9NT, UKChunyuan Chen - Department of Pediatrics, Third Xiangya Hospital, Central South University, Changsha 410013, ChinaNahal Mansouri - 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, IranSeyed Alireza Mahdaviani - 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, IranYuval Itan - St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York 10065, USABertrand Boisson - St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York 10065, USASatoshi Okada - St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York 10065, USALu Zeng - Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, ChinaXing Wang - Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, ChinaHui Jiang - BGI-Shenzhen, Shenzhen 518083, ChinaWenqiang Liu - Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, ChinaTiantian Han - Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, ChinaDelin Liu - Sangzhi County People's Hospital, Sangzhi 427100, ChinaTao Ma - Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, ChinaBo Wang - Genetics Laboratory, Hubei Maternal and Child Health Hospital, Wuhan, Hubei 430070, ChinaMugen Liu - Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, ChinaJing-Yu Liu - Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, ChinaQing K Wang - 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 Center for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USADilek Yalnizoglu - Immunology Division and Pediatric Neurology Department, Hacettepe University Children's Hospital, 06100 Ankara, TurkeyLilliana Radoshevich - Institut Pasteur, Bacteria-Cell Interactions Unit, 75724 Paris, FranceGilles Uzé - CNRS UMR5235, Montpellier II University, Place Eugène Bataillon, 34095 Montpellier, FrancePhilippe Gros - Department of Biochemistry, McGill University, Montreal, QC H3A 0G4, CanadaFlore Rozenberg - Paris Descartes University, 75006 Paris, FranceShen-Ying Zhang - St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York 10065, USAEmmanuelle Jouanguy - 1] Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France Paris Descartes University, Imagine Institute, 75015 Paris, FranceJacinta Bustamante - 1] Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France Paris Descartes University, Imagine Institute, 75015 Paris, France Center for the Study of Primary Immunodeficiencies, Necker Hospital for Sick Children, 75015 Paris, FranceAdolfo García-Sastre - 1] Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USALaurent Abel - 1] St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York 10065, USA Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France Paris Descartes University, Imagine Institute, 75015 Paris, FrancePierre Lebon - Paris Descartes University, 75006 Paris, FranceLuigi D Notarangelo - Division of Immunology, Children's Hospital Boston, Boston, Massachusetts 02115, USAYanick J Crow - 1] Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, M13 9NT, UK Paris Descartes University, Imagine Institute, 75015 Paris, France INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Imagine Institute, 75006 Paris, FranceStéphanie Boisson-Dupuis - 1] St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York 10065, USA Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France Paris Descartes University, Imagine Institute, 75015 Paris, FranceJean-Laurent Casanova - 1] Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France Paris Descartes University, Imagine Institute, 75015 Paris, France Howard Hughes Medical Institute, New York, New York 10065, USA Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, FranceSandra Pellegrini - 1] Institut Pasteur, Cytokine Signaling Unit, CNRS URA 1961, 75724 Paris, France
- Resource Type
- Journal article
- Publication Details
- Nature (London), Vol.517(7532), pp.89-93
- Publisher
- England
- DOI
- 10.1038/nature13801
- PMID
- 25307056
- PMCID
- PMC4303590
- ISSN
- 0028-0836
- eISSN
- 1476-4687
- Grant note
- P01AI090935 / NIAID NIH HHS R00 AI106942 / NIAID NIH HHS Howard Hughes Medical Institute 1P01AI076210-01A1 / NIAID NIH HHS R00AI106942-02 / NIAID NIH HHS P01 AI090935 / NIAID NIH HHS U19AI083025 / NIAID NIH HHS 309449 / European Research Council UL1 TR000043 / NCATS NIH HHS U19 AI083025 / NIAID NIH HHS 8UL1TR000043 / NCATS NIH HHS R37 AI095983 / NIAID NIH HHS R01 AI035237 / NIAID NIH HHS R37AI095983 / NIAID NIH HHS P01 AI076210 / NIAID NIH HHS
- Language
- English
- Date published
- 01/01/2015
- Academic Unit
- Molecular Physiology and Biophysics; Microbiology and Immunology
- Record Identifier
- 9984025459802771
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