Primary Immunodeficiency Group, Immunity and Inflammation Theme, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
Department of Infection and Tropical Medicine, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Sci Immunol. 2019 Dec 13;4(42). doi: 10.1126/sciimmunol.aav7501.
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 , a transcription factor that functions exclusively downstream of innate IFNs. Cells bearing STAT2 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 STAT2 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.
I 型干扰素（IFNα/β）活性过度与一系列人类疾病有关，但它的直接作用仍有待最终证实。我们研究了两名患有严重早发性自身炎症性疾病和 IFN 特征升高的兄弟姐妹。全外显子组测序显示，在 中存在一个共同的纯合错义 Arg148Trp 变体，这是一种转录因子，仅在先天 IFN 下游发挥作用。携带 STAT2 纯合性（而非杂合性）的细胞对 IFNα/β敏感，表现为 Janus 激酶-信号转导和转录激活物（STAT）信号和转录激活的延长。我们表明，这种 IFN 活性的增加是由于突变 STAT2 不能与泛素特异性蛋白酶 18 相互作用所致，后者是 IFNα/β 信号的关键 STAT2 依赖性负调节剂。这些观察结果揭示了 STAT2 在调节人类 IFNα/β 信号中的重要体内功能，为 IFNα/β 活性不受限制的严重病理后果提供了具体证据，并支持在 IFN 相关疾病中靶向该途径进行治疗的努力。
