Dataset Information


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

ABSTRACT: Excessive type I interferon (IFN?/?) 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 IFN?/?, 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 IFN?/? signaling. These observations reveal an essential in vivo function of STAT2 in the regulation of human IFN?/? signaling, providing concrete evidence of the serious pathological consequences of unrestrained IFN?/? activity and supporting efforts to target this pathway therapeutically in IFN-associated disease.


PROVIDER: S-EPMC7115903 | BioStudies | 2019-01-01

REPOSITORIES: biostudies

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