Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2
Open Access
- 6 December 2019
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Immunology
- Vol. 4 (42)
- https://doi.org/10.1126/sciimmunol.aav7501
Abstract
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.Keywords
Funding Information
- Wellcome Trust (211153/Z/18/Z)
- Wellcome Trust (207556/Z/17/Z)
- Wellcome Trust (101788/Z/13/Z)
- Medical Research Council (MR/N013840/1)
- Medical Research Council
- National Institute for Health Research (TRF-2016-09-002)
- Sir Jules Thorn Charitable Trust (12/JTA)
- European Research Council (GA 309449)
- Agence Nationale de la Recherche (ANR-10-IAHU-01)
- Agence Nationale de la Recherche (CE17001002)
- Kidney Research UK
- Agence Nationale de la Recherche (CE17001002)
- British Infection Association (Research Fellowship)
- Deutsche Forschungsgemeinschaft (GO 2955/1-1)
This publication has 61 references indexed in Scilit:
- STAT2 deficiency and susceptibility to viral illness in humansProceedings of the National Academy of Sciences of the United States of America, 2013
- INTERFEROME v2.0: an updated database of annotated interferon-regulated genesNucleic Acids Research, 2012
- Constitutive Type I Interferon Modulates Homeostatic Balance through Tonic SignalingImmunity, 2012
- USP18-Based Negative Feedback Control Is Induced by Type I and Type III Interferons and Specifically Inactivates Interferon α ResponsePLOS ONE, 2011
- Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasisThe Journal of Experimental Medicine, 2011
- Alpha Interferon Induces Long-Lasting Refractoriness of JAK-STAT Signaling in the Mouse Liver through Induction of USP18/UBP43Molecular and Cellular Biology, 2009
- The disease-protective complement factor H allotypic variant Ile62 shows increased binding affinity for C3b and enhanced cofactor activityHuman Molecular Genetics, 2009
- Trex1 Prevents Cell-Intrinsic Initiation of AutoimmunityCell, 2008
- UBP43 is a novel regulator of interferon signaling independent of its ISG15 isopeptidase activityThe EMBO Journal, 2006
- Comparative Protein Modelling by Satisfaction of Spatial RestraintsJournal of Molecular Biology, 1993