Role of ISG12 in cellular innate immune responses

描述（由申请人提供）：干扰素（ifn）是在先天免疫中起关键作用的多功能细胞因子。I型ifn （ifn -1、-2、-1等）表现出免疫调节、抗增殖和抗病毒活性，尽管基因敲除实验表明，在这些作用中，抗病毒功能对生存最为关键。ifn通过诱导离散的早期反应基因亚群（统称为ifn刺激基因（isg））来发挥作用。然而，到目前为止，人们对许多单个isg的确切功能仍然知之甚少。我们在多种正常和恶性人类细胞类型中进行了I型ifn调控基因的广泛基因表达谱分析。这些研究强调了常见（例如在所有细胞类型中诱导）和独特（细胞特异性）isg的大量谱。在这里，我们建议评估由ISG12a基因编码的蛋白质的生理功能，ISG12a基因是ifn诱导的基因，在我们的基因阵列研究中被认为是所有细胞类型中强烈诱导的ISG基因。我们最近的研究表明，ISG12a蛋白定位于线粒体膜，并且异位的ISG12a表达导致细胞对其他凋亡刺激的敏化。由于对病毒的凋亡反应是整个IFN反应的重要组成部分，我们假设ISG12a通过影响线粒体功能影响细胞对病毒感染的反应能力，并可能调节凋亡反应。因此，我们建议通过开展探索性研究来评估内源性ISG12a在ifn依赖性线粒体反应和抗病毒作用中的生理重要性。目的：探讨ISG12a在ifn诱导的细胞和线粒体变化中的意义。确定ISG12a诱导对抗病毒和其他先天免疫反应的意义公共卫生相关性：机体对入侵生物体（包括病毒和细菌）的反应能力取决于免疫细胞和体内其他细胞类型的协调作用。受病毒感染的细胞产生干扰素，不仅会上调机体对其他病毒的感知和反应能力，还会上调机体对其他入侵微生物的反应能力。我们已经确定了一种干扰素诱导的蛋白，称为ISG12a，我们认为它参与了这种致敏过程，更好地了解ISG12a对细胞的影响，将有助于更好地了解人体如何调节对病毒和其他病原体的反应。

DESCRIPTION (provided by applicant): Interferons (IFNs) are multifunctional cytokines that play a critical role in innate immunity. Type I IFNs (IFNs-1, -2, -I and others) exhibit immunomodulatory, antiproliferative and antiviral activities, although gene knockout experiments have suggested that, among these effects, the antiviral function is most critical for survival. IFNs elicit their effects through the induction of discreet subsets of early response genes, known collectively as IFN-stimulated genes (ISGs). To date, however, the precise functions of many individual ISGs remain poorly understood. We have performed extensive gene expression profiling of genes regulated by type I IFNs in a variety of normal and malignant human cell types. These studies have highlighted large repertoires of both common (e.g. induced in all cell types) and unique (cell-specific) ISGs. Here, we propose to assess the physiological function of the protein encoded by the ISG12a gene, an IFN-induced gene that was implicated in our gene array studies as an ISG strongly induced in all cell types. Our recent studies have shown that the ISG12a protein is localized to the mitochondrial membrane, and that ectopic ISG12a expression results in a sensitization of cells to other apoptotic stimuli. Since apoptotic responses to virus are an important component of an overall IFN response, we hypothesize that ISG12a influences the ability of cells to respond to viral infections by impacting mitochondrial function, and possibly regulating apoptotic responses. Thus, we propose to evaluate the physiological importance of endogenous ISG12a in both IFN-dependent mitochondrial responses and in antiviral effects by conducting exploratory studies that encompass these specific aims: Aim 1. To determine the significance of ISG12a in IFN-induced cellular and mitochondrial changes Aim 2. To determine the significance of ISG12a induction on antiviral and other innate immune responses PUBLIC HEALTH RELEVANCE: The ability of the body to respond to invading organisms, including virus and bacteria, depends on the coordinated actions of both immune cells and other cell types in the body. Production of interferon by virally infected cells upregulates the body's ability to sense and respond not only to other viruses, but also to other invading microorganisms. We have identified an interferon-induced protein, called ISG12a, that we feel is involved in this sensitization process, and better understanding of ISG12a's effects on cells should lead to improved understanding of how the body regulates responses to virus and other pathogens.