Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2, 2019, Duncan et al

Andy · Dec 30, 2019

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.

Abstract
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 STAT2, a transcription factor that functions exclusively downstream of innate IFNs. Cells bearing STAT2R148W 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 STAT2R148W 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.
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Paywall, https://immunology.sciencemag.org/content/4/42/eaav7501
Sci hub, https://sci-hub.se/10.1126/sciimmunol.aav7501

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Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2, 2019, Duncan et al

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Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2, 2019, Duncan et al

Andy Committee Member

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