Signal Transduction Mechanisms of Type I IFNs

我们早期的工作确定了转录的信号转导子和激活子 （STAT）2作为促进I型干扰素诱导的细胞凋亡的关键介质。这 这是一个有趣的观察，因为IFN是已知激活STAT 2的唯一细胞因子。我们最 最近的工作已经确定了STAT 2中的一个敏感的保守区域，该区域在IFN 刺激可以决定细胞命运。在我们的细胞系模型中， 治疗时，在STAT 2的Src同源区（SH 2）-2结构域中引入突变， 肿瘤细胞经历细胞凋亡，如果它们表达野生型形式的STAT 2， 只有生长被这种细胞因子阻止。根据我们的研究，我们得出结论， 氨基酸改变延长了STAT 1和STAT 2之间的物理相互作用。仅此一项 允许STAT异源二聚体增加其在细胞核中的持续时间，同时增加 IFN刺激基因的转录水平。这些发现促使我们研究 在12%的人中检测到一种STAT 2单核苷酸多态性（SNP）， 人口该SNP（M594 I）是非同义的，并且在STAT 2的SH 2结构域中发现。我们 测量了其转录功能，并因此测量了I型IFN生物学应答， 野生型STAT 2。我们的研究表明，这种SNP增强了型胶原蛋白的抗增殖作用。 I IFN。更有趣的是，已知的肿瘤细胞生长被IFN型抑制，当它们 表达该SNP的小鼠变得对该细胞因子的凋亡效应敏感。建立 为了研究这种SNP与IFN治疗之间的关系，我们分析了一组丙型肝炎患者， 接受干扰素治疗以控制病毒感染。STAT 2杂合子患者 M594 I对IFN治疗的反应优于STAT 2纯合子。我们共同 研究结果强烈表明，STAT 2是细胞凋亡激活的关键成分 由I型IFN和特异性STAT 2突变诱导的免疫应答可能有益于或适得其反， 一个正在接受干扰素治疗的病人

Our earlier work identified the signal transducer and activator of transcription (STAT)2 as a critical mediator in the promotion of type I interferon-induced apoptosis. This is an interesting observation as IFNs are the only cytokines known to activate STAT2. Our most recent work has identified a sensitive conserved region in STAT2 that following IFN stimulation can determine cell fate. In our cell line model, in response to IFN-alpha treatment, a mutation introduced in the Src-homology-region (SH2)-2 domain of STAT2 makes tumor cells undergo apoptosis that if they expressed the wild type form of STAT2, they are only growth arrested by this cytokine. Based on our studies, we concluded that this single amino acid change prolonged the physical interaction between STAT1 and STAT2. This alone allowed the STAT heterodimer to increase its duration in the nucleus while increasing the transcriptional levels of IFN-stimulated genes. These findings prompted us to examine carefully one STAT2 single nucleotide polymorphisms (SNP)detected in 12% in the human population. This SNP (M594I) is non-synonimous and found in the SH2 domain of STAT2. We measured its transcriptional function and consequently type I IFN biological responses against wild type STAT2. Our studies show that this SNP enhances the antiproliferative effects of type I IFNs. More interestingly, tumor cells known to be growth arrested by type IFNs, when they expressed this SNP became susceptible to the apoptotic effects of this cytokine. To establish an association between this SNP and IFN therapy, we analyzed a cohort of Hepatitis C patients who had received IFN treatment to control viral infection. Patients heterozygote for STAT2 M594I responded better to IFN therapy that those who were STAT2 homozygote. Collectively our findings strongly suggest that STAT2 is a critical component in the activation of apoptosis induced by type I IFNs and specific STAT2 mutations may be beneficial or counterproductive to a patient being treated with IFN.