Lookup NU author(s): Dr Christopher Duncan,
Dr Rui Chen,
Dr Florian Gothe,
Dr Vicky Brocklebank,
Dr Meghan Acres,
Dr Aneta Mikulasova,
Dr Ruyue Sun,
Professor Claire Harris,
Dr Karin Engelhardt,
Professor David Kavanagh,
Professor Sophie Hambleton
This is the authors' accepted manuscript of an article that has been published in its final definitive form by American Association for the Advancement of Science, 2019.
For re-use rights please refer to the publisher's terms and conditions.
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 STAT2R148Win homozygosity (but not heterozygosity) were hypersensitive to IFNα/β, manifest as prolonged JAK-STAT signaling and transcriptional activation. We show that this gain of IFN activity results from the failure of mutant STAT2R148Wto interact with ubiquitin specific protease 18 (USP18), a key STAT2-dependent negative regulator of IFNα/β signaling. These observations reveal an essential in vivofunction 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.
Author(s): Duncan CJA, Thompson BJ, Chen R, Rice GI, Gothe F, Young DF, Lovell SC, Shuttleworth VG, Brocklebank V, Corner B, Skelton AJ, Bondet V, Coxhead J, Duffy D, Fourrage C, Livingston JH, Pavaine J, Cheesman E, Bitetti S, Grainger A, Acres M, Innes BA, Mikulasova A, Sun R, Hussain H, Wright R, Wynn R, Zarhrate M, Zeef LAH, Wood K, Hughes SM, Harris CL, Engelhardt KE, Crow YJ, Randall RE, Kavanagh D, Hambleton S, Briggs TA
Publication type: Article
Publication status: Published
Journal: Science Immunology
Online publication date: 13/12/2019
Acceptance date: 14/11/2019
Date deposited: 27/11/2019
ISSN (electronic): 2470-9468
Publisher: American Association for the Advancement of Science
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