Impaired response to interferon-α/β and lethal viral disease in human STAT1 deficiency
Impaired response to interferon-α/β and lethal viral disease in human STAT1 deficiency
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DOI：
10.1038/ng1097
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发表时间：
2003-03-01
期刊：
影响因子：
30.8
通讯作者：
Casanova, JL
中科院分区：
文献类型：
--
作者：
Dupuis, S;Jouanguy, E;Casanova, JL
干扰素- α / β - ifn - α / β和ifn - γ的受体激活Janus激酶信号转换器和转录激活因子（JAK-STAT）信号通路的成分，导致至少两种转录因子复合物的形成(1)。STAT1与STAT2和p48/IRF-9相互作用形成转录因子ifn刺激基因因子3 （ISGF3）。STAT1二聚体形成γ活化因子（GAF）。ISGF3主要由IFN- α / β诱导，而GAF主要由IFN- γ诱导，尽管这两种因子都可以被两种类型的IFN激活。ifn - γ受体（ifn - γ - mar）任一链突变的个体易受分枝杆菌感染（2-5）。在其他分枝杆菌疾病患者中发现了一种杂合子STAT1突变，该突变损害GAF而不损害ISGF3的激活(6)。ifn - α / β信号通路中没有有害突变的个体被描述。我们在此报告两个不相关的婴儿纯合的突变STAT1等位基因。ifn - α / β和ifn - γ都不能激活含有stat1的转录因子。与ifn - γ缺乏症的个体一样，两个婴儿都患有分枝杆菌疾病，但与ifn - γ缺乏症的个体不同，两个婴儿都死于病毒性疾病。重组ifn - α / β在两个个体的细胞系中没有抑制病毒增殖。因此，stat1依赖性对人类ifn - α / β的反应的遗传性损伤导致对病毒性疾病的易感性。
The receptors for interferon-alpha/beta IFN-alpha/beta and IFN-gamma activate components of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway, leading to the formation of at least two transcription factor complexes(1). STAT1 interacts with STAT2 and p48/IRF-9 to form the transcription factor IFN-stimulated gene factor 3 (ISGF3). STAT1 dimers form gamma-activated factor (GAF). ISGF3 is induced mainly by IFN-alpha/beta and GAF by IFN-gamma, although both factors can be activated by both types of IFN. Individuals with mutations in either chain of the IFN-gamma receptor (IFN-gammaR) are susceptible to infection with mycobacteria(2-5). A heterozygous STAT1 mutation that impairs GAF but not ISGF3 activation has been found in other individuals with mycobacterial disease(6). No individuals with deleterious mutations in the IFN-alpha/beta signaling pathway have been described. We report here two unrelated infants homozygous with respect to mutated STAT1 alleles. Neither IFN-alpha/beta nor IFN-gamma activated STAT1-containing transcription factors. Like individuals with IFN-gammaR deficiency, both infants suffered from mycobacterial disease, but unlike individuals with IFN-gammaR deficiency, both died of viral disease. Viral multiplication was not inhibited by recombinant IFN-alpha/beta in cell lines from the two individuals. Inherited impairment of the STAT1-dependent response to human IFN-alpha/beta thus results in susceptibility to viral disease.