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Nature. 2015 Jan 1;517(7532):89-93. doi: 10.1038/nature13801. Epub 2014 Oct 12.

Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation.

Author information

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.
2
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.
3
Institut Pasteur, Cytokine Signaling Unit, CNRS URA 1961, 75724 Paris, France.
4
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.
5
1] Division of Immunology, Children's Hospital Boston, Boston, Massachusetts 02115, USA [2] Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16132 Genoa, Italy.
6
Immunology Division and Pediatric Neurology Department, Hacettepe University Children's Hospital, 06100 Ankara, Turkey.
7
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.
8
Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, M13 9NT, UK.
9
Department of Pediatrics, Third Xiangya Hospital, Central South University, Changsha 410013, China.
10
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York 10065, USA.
11
BGI-Shenzhen, Shenzhen 518083, China.
12
Sangzhi County People's Hospital, Sangzhi 427100, China.
13
Genetics Laboratory, Hubei Maternal and Child Health Hospital, Wuhan, Hubei 430070, China.
14
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 [2] Center for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
15
Institut Pasteur, Bacteria-Cell Interactions Unit, 75724 Paris, France.
16
CNRS UMR5235, Montpellier II University, Place Eugène Bataillon, 34095 Montpellier, France.
17
Department of Biochemistry, McGill University, Montreal, QC H3A 0G4, Canada.
18
Paris Descartes University, 75006 Paris, France.
19
1] Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France [2] Paris Descartes University, Imagine Institute, 75015 Paris, France.
20
1] Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France [2] Paris Descartes University, Imagine Institute, 75015 Paris, France [3] Center for the Study of Primary Immunodeficiencies, Necker Hospital for Sick Children, 75015 Paris, France.
21
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] Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
22
1] St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York 10065, USA [2] Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France [3] Paris Descartes University, Imagine Institute, 75015 Paris, France.
23
Division of Immunology, Children's Hospital Boston, Boston, Massachusetts 02115, USA.
24
1] Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, M13 9NT, UK [2] Paris Descartes University, Imagine Institute, 75015 Paris, France [3] INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Imagine Institute, 75006 Paris, France.
25
1] Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France [2] Paris Descartes University, Imagine Institute, 75015 Paris, France [3] Howard Hughes Medical Institute, New York, New York 10065, USA [4] Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France [5].
26
1] Institut Pasteur, Cytokine Signaling Unit, CNRS URA 1961, 75724 Paris, France [2].

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.

PMID:
25307056
PMCID:
PMC4303590
DOI:
10.1038/nature13801
[Indexed for MEDLINE]
Free PMC Article

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