Homozygous STAT2 gain-of-function mutation by loss of USP18 activity in a patient with type I interferonopathy
Homozygous STAT2 gain-of-function mutation by loss of USP18 activity in a patient with type I interferonopathy
复制标题
DOI：
10.1084/jem.20192319
复制
发表时间：
2020-05-01
影响因子：
15.3
通讯作者：
Bogunovic, Dusan
中科院分区：
文献类型：
--
作者：
Gruber, Conor;Martin-Fernandez, Marta;Bogunovic, Dusan
I 型干扰素病是单基因疾病，其特征是 I 型干扰素 (IFN-I) 细胞因子活性增强。遗传性USP18和ISG15缺陷通过阻止对IFN-I的晚期反应的调节而成为I型干扰素病的基础。具体而言，被ISG15稳定的USP18在空间上阻碍JAK1与IFN-I受体的IFNAR2亚基结合。我们报道了一名因 STAT2 纯合错义突变 (R148Q) 导致的自身炎症死亡的婴儿。该变体是功能获得（GOF），用于诱导对 IFN-I 的晚期而非早期反应。令人惊讶的是，该突变并没有增强负责 IFN-I 刺激基因诱导的包含 STAT2 的转录复合物的内在活性。相反，STAT2 R148Q 变体是 GOF，因为它无法正确地将 USP18 转运至 IFNAR2，从而阻止 USP18 对 IFN-I 的反应进行负调节。 STAT2 R148Q 的纯合性代表了遗传性 USP18 缺陷的一种新的分子和临床表型，它与遗传性 ISG15 缺陷一起定义了一组 I 型干扰素病，其特征是对 IFN-I 的晚期细胞反应调节受损。
Type I interferonopathies are monogenic disorders characterized by enhanced type I interferon (IFN-I) cytokine activity. Inherited USP18 and ISG15 deficiencies underlie type I interferonopathies by preventing the regulation of late responses to IFN- I. Specifically, USP18, being stabilized by ISG15, sterically hinders JAK1 from binding to the IFNAR2 subunit of the IFN-I receptor. We report an infant who died of autoinflammation due to a homozygous missense mutation (R148Q) in STAT2. The variant is a gain of function (GOF) for induction of the late, but not early, response to IFN-I. Surprisingly, the mutation does not enhance the intrinsic activity of the STAT2-containing transcriptional complex responsible for IFN-I-stimulated gene induction. Rather, the STAT2 R148Q variant is a GOF because it fails to appropriately traffic USP18 to IFNAR2, thereby preventing USP18 from negatively regulating responses to IFN-I. Homozygosity for STAT2 R148Q represents a novel molecular and clinical phenocopy of inherited USP18 deficiency, which, together with inherited ISG15 deficiency, defines a group of type I interferonopathies characterized by an impaired regulation of late cellular responses to IFN-I.