Research ArticleINTERFERON SIGNALING

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

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Science Immunology  13 Dec 2019:
Vol. 4, Issue 42, eaav7501
DOI: 10.1126/sciimmunol.aav7501

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Interferon Insight

Uncontrolled type I IFN activity has been linked to several human pathologies, but evidence implicating this cytokine response directly in disease has been limited. Here, Duncan et al. identified a homozygous missense mutation in STAT2 in siblings with severe early-onset autoinflammatory disease and elevated IFN activity. STAT2 is a transcription factor that functions downstream of IFN, and this STAT2R148W variant was associated with elevated responses to IFNα/β and prolonged JAK-STAT signaling. Unlike wild-type STAT2, the STAT2R148W variant could not interact with ubiquitin-specific protease 18, which prevented STAT2-dependent negative regulation of IFNα/β signaling. These findings provide insight into the role of STAT2 in regulating IFNα/β signaling in humans.

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