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

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.
Mesh Terms:
Germ-Line Mutation, Humans, Immune System Diseases, Infant, Interferon Type I, Male, STAT2 Transcription Factor, Signal Transduction
Sci Immunol
Date: Dec. 13, 2018
Download Curated Data For This Publication
223408
Switch View:
  • Interactions 2