Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2.,Science Immunology

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Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2.
Science Immunology ( IF 24.8 ) Pub Date : 2019-12-13 , DOI: 10.1126/sciimmunol.aav7501
Christopher J A Duncan _{1,

2} , Benjamin J Thompson ₁ , Rui Chen ₁ , Gillian I Rice ₃ , Florian Gothe _{1,

4} , Dan F Young ₅ , Simon C Lovell ₃ , Victoria G Shuttleworth ₆ , Vicky Brocklebank ₆ , Bronte Corner ₆ , Andrew J Skelton ₁ , Vincent Bondet ₇ , Jonathan Coxhead ₈ , Darragh Duffy ₇ , Cecile Fourrage ₉ , John H Livingston ₁₀ , Julija Pavaine _{11,

12} , Edmund Cheesman ₁₃ , Stephania Bitetti ₁₃ , Angela Grainger ₁ , Meghan Acres ₁ , Barbara A Innes ₁ , Aneta Mikulasova ₁ , Ruyue Sun ₆ , Rafiqul Hussain ₇ , Ronnie Wright _{3,

14} , Robert Wynn ₁₅ , Mohammed Zarhrate ₁₆ , Leo A H Zeef ₁₇ , Katrina Wood ₁₈ , Stephen M Hughes ₁₉ , Claire L Harris ₆ , Karin R Engelhardt ₁ , Yanick J Crow _{20,

21,

22} , Richard E Randall ₅ , David Kavanagh _{6,

23} , Sophie Hambleton _{1,

24} , Tracy A Briggs _{3,

14}

Affiliation

Primary Immunodeficiency Group, Immunity and Inflammation Theme, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
Department of Infection and Tropical Medicine, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, UK.
Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität Munich, Munich, Germany.
School of Biology, University of St. Andrews, St. Andrews, UK.
Complement Therapeutics Research Group, Immunity and Inflammation Theme, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
Immunobiology of Dendritic Cells, Institut Pasteur, Paris, France.
Genomics Core Facility, Biosciences Institute, Newcastle University, UK.
Plateforme Bioinformatique, Institut Imagine, Paris, France.
Department of Paediatric Neurology, Leeds General Infirmary, Leeds, UK.
Academic Unit of Paediatric Radiology, Royal Manchester Children's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
Division of Informatics, Imaging and Data Sciences, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Department of Paediatric Histopathology, Central Manchester University Foundation NHS Trust, Manchester, UK.
Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
Department of Paediatric Blood and Marrow Transplant, Royal Manchester Children's Hospital, Oxford Rd., Manchester, UK.
Genomics Core Facility, Institut Imagine, Paris, France.
Bioinformatics Core Facility, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Department of Pathology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Immunology Department, Royal Manchester Children's Hospital, Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
MRC Institute of Genetics and Molecular Medicine, Centre for Genomic and Experimental Medicine, The University of Edinburgh, Edinburgh, UK.
Laboratory of Neurogenetics and Neuroinflammation, Institut Imagine, Paris, France.
Paris Descartes University, Sorbonne-Paris-Cité, Paris, France.
National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne Hosptials NHS Foundation Trust, Newcastle upon Tyne, UK.
Children's Immunology Service, Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.

Excessive type I interferon (IFNα/β) activity is implicated in a spectrum of human disease, yet its direct role remains to be conclusively proven. We investigated two siblings with severe early-onset autoinflammatory disease and an elevated IFN signature. Whole-exome sequencing revealed a shared homozygous missense Arg148Trp variant in STAT2, a transcription factor that functions exclusively downstream of innate IFNs. Cells bearing STAT2R148W in homozygosity (but not heterozygosity) were hypersensitive to IFNα/β, which manifest as prolonged Janus kinase-signal transducers and activators of transcription (STAT) signaling and transcriptional activation. We show that this gain of IFN activity results from the failure of mutant STAT2R148W to interact with ubiquitin-specific protease 18, a key STAT2-dependent negative regulator of IFNα/β signaling. These observations reveal an essential in vivo function of STAT2 in the regulation of human IFNα/β signaling, providing concrete evidence of the serious pathological consequences of unrestrained IFNα/β activity and supporting efforts to target this pathway therapeutically in IFN-associated disease.

更新日期：2019-12-17

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