Signal Transduction Mechanisms of Type I IFNs

I型干扰素（IFN）的主要生物学作用之一是它们对肿瘤细胞施加的抗生长和抗肿瘤作用，这一主要性质引起了癌症领域许多人的注意，并允许IFN用于治疗多种癌症的临床应用。IFN的生长抑制机制是复杂的，因为这些细胞因子可以通过促进细胞周期停滞或通过触发程序性细胞死亡或“凋亡”来引发它们的抗生长作用。后一种细胞死亡机制仍然知之甚少。我们的工作已经确定了信号转导和转录激活因子（STAT）2作为一个重要的介质，在促进I型干扰素诱导的细胞凋亡。在我们的细胞系模型中，STAT2的丢失阻止了由I型IFN触发的线粒体死亡途径的激活。最重要的是，我们已经确定了一个新的基序STAT2控制IFN诱导的细胞凋亡。这些发现促使我们仔细研究了一些STAT2单核苷酸多态性（SNPs）最近在人群中发现，因为这些突变可能有能力改变STAT2的转录功能，从而改变I型IFN的生物反应。到目前为止，我们已经确定了这些STAT2 SNP之一，它增强了I型IFN的抗增殖作用。总的来说，我们的研究结果强烈表明，STAT2是一个关键的组成部分，在激活细胞凋亡诱导的I型IFN和特定的STAT2突变可能是适得其反或有益的主机。

One of the major biological actions of type I interferons (IFNs) is the antigrowth and antitumor effects they exert on tumor cells, a major property that captured the attention of many in the cancer field and allowed the clinical application of IFNs for the treatment of a variety of cancers. The mechanisms of growth inhibition of IFNs are complex as these cytokines can elicit their antigrowth actions by promoting cell cycle arrest or by triggering programmed cell death or "apoptosis". This latter cell death mechanism remains poorly understood. Our work has identified the signal transducer and activator of transcription (STAT)2 as a critical mediator in the promotion of type I interferon-induced apoptosis. In our cell line model, loss of STAT2 prevents the activation of the mitochondrial death pathway triggered by type I IFNs. Most importantly, we have identified a novel motif in STAT2 that controls IFN-induced apoptosis. These findings have prompted us to examine carefully a number of STAT2 single nucleotide polymorphisms (SNPs) recently identified in the human population as these mutations might have the capacity to alter STAT2 transcriptional function and consequently type I IFN biological responses. Thus far we have characterized one of these STAT2 SNPs, which enhance the antiproliferative effects of type I IFNs. 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 counterproductive or beneficial to the host.