Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2.
Sci Immunol
; 4(42)2019 12 13.
Article
en En
| MEDLINE
| ID: mdl-31836668
ABSTRACT
Excessive type I interferon (IFNα/ß) 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/ß, 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/ß signaling. These observations reveal an essential in vivo function of STAT2 in the regulation of human IFNα/ß signaling, providing concrete evidence of the serious pathological consequences of unrestrained IFNα/ß activity and supporting efforts to target this pathway therapeutically in IFN-associated disease.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Interferón Tipo I
/
Factor de Transcripción STAT2
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Enfermedades del Sistema Inmune
Límite:
Humans
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Infant
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Male
Idioma:
En
Revista:
Sci Immunol
Año:
2019
Tipo del documento:
Article