title: Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation.
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.
authors.affiliation: 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.
authors.forename: Xianqin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: 1] St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York 10065, USA [2] Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Dusan
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authors.lastname: Bogunovic
authors.affiliation: Institut Pasteur, Cytokine Signaling Unit, CNRS URA 1961, 75724 Paris, France.
authors.forename: Béatrice
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authors.affiliation: Institut Pasteur, Cytokine Signaling Unit, CNRS URA 1961, 75724 Paris, France.
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authors.lastname: Francois-Newton
authors.affiliation: 1] Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [2] Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [3] Microbiology Training Area, Graduate School of Biomedical Sciences of Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
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authors.affiliation: 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.
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authors.affiliation: Institut Pasteur, Cytokine Signaling Unit, CNRS URA 1961, 75724 Paris, France.
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authors.affiliation: Immunology Division and Pediatric Neurology Department, Hacettepe University Children's Hospital, 06100 Ankara, Turkey.
authors.forename: Ozden
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authors.affiliation: 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.
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authors.affiliation: Immunology Division and Pediatric Neurology Department, Hacettepe University Children's Hospital, 06100 Ankara, Turkey.
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authors.affiliation: 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.
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authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York 10065, USA.
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authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York 10065, USA.
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authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York 10065, USA.
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authors.affiliation: 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.
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authors.affiliation: 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.
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authors.affiliation: 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.
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authors.affiliation: 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.
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authors.affiliation: 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.
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authors.affiliation: 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.
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authors.affiliation: 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.
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mesh_terms: D000293:Adolescent; D000483:Alleles; D002648:Child; D016207:Cytokines / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010450:Endopeptidases / Q000737:chemistry / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D007370:Interferon Type I / Q000276:immunology* / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism*; D008297:Male; D010375:Pedigree; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D015398:Signal Transduction; D043222:Ubiquitin Thiolesterase; D054875:Ubiquitination; D014452:Ubiquitins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014780:Viruses / Q000276:immunology
chemical_list: D016207:Cytokines; D007370:Interferon Type I; D044786:S-Phase Kinase-Associated Proteins; D014452:Ubiquitins; C074034:ISG15 protein, human; D010450:Endopeptidases; C485560:USP18 protein, human; D043222:Ubiquitin Thiolesterase