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

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 hom...

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Vydané v:	Science immunology Ročník 4; číslo 42
Hlavní autori:	Duncan, Christopher J A, Thompson, Benjamin J, Chen, Rui, Rice, Gillian I, Gothe, Florian, Young, Dan F, Lovell, Simon C, Shuttleworth, Victoria G, Brocklebank, Vicky, Corner, Bronte, Skelton, Andrew J, Bondet, Vincent, Coxhead, Jonathan, Duffy, Darragh, Fourrage, Cecile, Livingston, John H, Pavaine, Julija, Cheesman, Edmund, Bitetti, Stephania, Grainger, Angela, Acres, Meghan, Innes, Barbara A, Mikulasova, Aneta, Sun, Ruyue, Hussain, Rafiqul, Wright, Ronnie, Wynn, Robert, Zarhrate, Mohammed, Zeef, Leo A H, Wood, Katrina, Hughes, Stephen M, Harris, Claire L, Engelhardt, Karin R, Crow, Yanick J, Randall, Richard E, Kavanagh, David, Hambleton, Sophie, Briggs, Tracy A
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 13.12.2019
Predmet:	Germ-Line Mutation Humans Immune System Diseases - genetics Immune System Diseases - immunology Infant Interferon Type I - immunology Male Signal Transduction STAT2 Transcription Factor - genetics
ISSN:	2470-9468, 2470-9468
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Shrnutí:	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 , a transcription factor that functions exclusively downstream of innate IFNs. Cells bearing STAT2 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 STAT2 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.
Bibliografia:	ObjectType-Case Study-2 SourceType-Scholarly Journals-1 ObjectType-Feature-4 content type line 23 ObjectType-Report-1 ObjectType-Article-3
ISSN:	2470-9468 2470-9468
DOI:	10.1126/sciimmunol.aav7501