Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2
Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2
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DOI：
10.1126/sciimmunol.aav7501
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发表时间：
2019-12-01
影响因子：
24.8
通讯作者：
Briggs, Tracy A.
中科院分区：
文献类型：
--
作者：
Duncan, Christopher J. A.;Thompson, Benjamin J.;Briggs, Tracy A.
I 型干扰素 (IFN α/β) 活性过高与一系列人类疾病有关，但其直接作用仍有待最终证实。我们调查了两个患有严重早发性自身炎症性疾病和 IFN 信号升高的兄弟姐妹。全外显子组测序揭示了 STAT2 中共有的纯合错义 Arg148Trp 变体，STAT2 是一种专门在先天 IFN 下游发挥作用的转录因子。带有纯合性（而非杂合性）STAT2（R148W）的细胞对IFNα/β过敏，这表现为Janus激酶信号转导子和转录激活子（STAT）信号传导和转录激活延长。我们发现，IFN 活性的增加是由于突变体 STAT2(R148W) 未能与泛素特异性蛋白酶 18 相互作用所致，泛素特异性蛋白酶 18 是 IFN α/β 信号传导的关键 STAT2 依赖性负调节因子。这些观察结果揭示了 STAT2 在调节人 IFN α/β 信号传导中的重要体内功能，为不受限制的 IFN α/β 活性的严重病理后果提供了具体证据，并支持在 IFN 相关疾病中针对该通路进行治疗的努力。
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.