Signal Transduction Mechanisms of Type I IFNs

我们早期的工作确定了信号转导子和转录激活子2 STAT2作为促进I型干扰素（IFN）诱导的细胞凋亡的关键介质。 这是一个有趣的观察结果，因为IFN是已知激活STAT2的唯一细胞因子。我们 最近的工作已经确定了STAT2中的一个敏感的保守区域，该区域可以决定细胞的增殖， IFN刺激后的命运。在我们的细胞系模型中，响应于IFN-α治疗， 在STAT2的Src同源区2（SH2）结构域中引入突变产生肿瘤细胞 只有在表达野生型STAT2的情况下，细胞才会发生凋亡;否则， 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STAT1和STAT2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%的人中检测到一个STAT2单核苷酸多态性（SNP）， 人口该SNP（M594I）是非同义的，并且在STAT2的SH2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STAT2。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，已知肿瘤细胞的生长被IFN型抑制， 当它们表达这种SNP时，变得容易受到这种细胞因子的凋亡作用。到 为了建立该SNP与IFN治疗之间的关联，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的患者。杂合子患者 STAT2 M594I对IFN治疗的反应优于STAT2纯合子。 总的来说，我们的研究结果强烈表明，STAT2是一个关键组成部分，在 由I型IFN和特异性STAT2突变诱导的细胞凋亡的激活可能是有益的 或对用IFN治疗的患者产生反作用。

Our earlier work identified the signal transducer and activator of transcription 2 (STAT2) as a critical mediator in the promotion of type I interferon (IFN)-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 can determine cell fate following IFN stimulation. In our cell line model, in response to IFN-alpha treatment, a mutation introduced in the Src homology region 2 (SH2) domain of STAT2 made tumor cells undergo apoptosis only if they expressed the wild-type form of STAT2; otherwise the cells were 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 polymorphism (SNP)detected in 12% in the human population. This SNP (M594I) is non-synonymous and is 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 that were 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 than 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.