Signal Transduction Mechanisms of Type I IFNs

我们早期的工作确定信号转导和转录激活因子(STAT)2是促进I型干扰素诱导的细胞凋亡的关键介质。这是一个有趣的观察，因为IFN是唯一已知的激活STAT2的细胞因子。我们最新的工作已经在STAT2中发现了一个敏感的保守区，在干扰素刺激后可以决定细胞的命运。在我们的细胞系模型中，作为对干扰素-α处理的响应，在STAT2的Src同源区(SH2)-2结构域引入的突变使肿瘤细胞发生凋亡，如果它们表达野生型的STAT2，它们只会被这种细胞因子抑制生长。根据我们的研究，我们得出结论，这种单一氨基酸的变化延长了STAT1和STAT2之间的物理相互作用。仅此一项就允许STAT异源二聚体增加其在细胞核中的持续时间，同时增加干扰素刺激基因的转录水平。这些发现促使我们仔细检查在12%的人群中检测到的一种STAT2单核苷酸多态(SNP)。这个SNP(M594I)是非同义的，发现于STAT2的SH2结构域。我们测量了它的转录功能，从而检测了I型干扰素对野生型STAT2的生物学反应。我们的研究表明，这种SNP增强了I型IFN的抗增殖作用。更有趣的是，已知的被IFN类型阻止生长的肿瘤细胞，当它们表达这种SNP时，对这种细胞因子的凋亡效应变得敏感。为了建立这种SNP和干扰素治疗之间的联系，我们分析了一组接受干扰素治疗以控制病毒感染的丙型肝炎患者。STAT2 M594I杂合子患者对干扰素治疗的疗效好于STAT2纯合子患者。总之，我们的发现有力地表明，STAT2在I型IFN诱导的细胞凋亡的激活过程中是一个关键成分，而特定的STAT2突变对接受干扰素治疗的患者可能是有利的，也可能是相反的。

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.