期刊
SCIENCE IMMUNOLOGY
卷 4, 期 42, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciimmunol.aav7501
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资金
- British Infection Association
- Wellcome Trust [211153/Z/18/Z, 207556/Z/17/Z, 101788/Z/13/Z]
- Sir Jules Thorn Trust [12/JTA]
- UK National Institute of Health Research [TRF-2016-09-002]
- NIHR Manchester Biomedical Resource Centre
- Medical Research Foundation
- Medical Research Council [MRC] [MR/N013840/1]
- MRC/Kidney Research UK [MR/R000913/1]
- Deutsche Forschungsgemeinschaft [GO 2955/1-1]
- Agence Nationale de la Recherche [ANR-10-IAHU-01, CE17001002]
- European Research Council [GA 309449, 786142-E-T1IFNs]
- Newcastle University
- ImmunoQure for provision of antibodies
- Medical Research Council
- Kidney Research UK
- Macular Society
- NCKRF
- AMD Society
- Complement UK
- Academy of Medical Sciences (AMS) [AMS-SGCL11-Duncan] Funding Source: researchfish
- Wellcome Trust [211153/Z/18/Z, 207556/Z/17/Z] Funding Source: researchfish
- National Institutes of Health Research (NIHR) [TRF-2016-09-002] Funding Source: National Institutes of Health Research (NIHR)
- MRC [MC_PC_16054, 1793967, MR/R000913/1] Funding Source: UKRI
Excessive type I interferon (IFN alpha/beta) 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 STAT2(R148W) in homozygosity (but not heterozygosity) were hypersensitive to IFN alpha/beta, 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 STAT2(R148W) to interact with ubiquitin-specific protease 18, a key STAT2-dependent negative regulator of IFN alpha/beta signaling. These observations reveal an essential in vivo function of STAT2 in the regulation of human IFN alpha/beta signaling, providing concrete evidence of the serious pathological consequences of unrestrained IFN alpha/beta activity and supporting efforts to target this pathway therapeutically in IFN-associated disease.
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