ISG15 and Protein ISGylation in Cancer

标题：癌症中的ISG15和蛋白ISG化 摘要 这项研究的长期目标是了解ISG15相关蛋白在翻译后的作用 修饰(ISG，一种泛素样修饰)在癌症发展和预后中的作用。近几年来 我们对I型干扰素(干扰素)在癌症中的信号传递的了解迅速扩大。它现在被认为是 干扰素在癌症的发展和癌症治疗的疗效中起着重要作用。这个 干扰素的生物活性依赖于多种干扰素刺激基因(ISGs)的表达。然而，的功能是 与干扰素在癌症中的作用相关的不同ISGs仍然很大程度上是未知的。ISG15是主要的 ISGS。它的表达被干扰素和任何促进干扰素产生的细胞压力强烈上调。 此外，大多数参与蛋白质ISG化的酶也是由ISGs编码的。因此， 蛋白质ISG化受到干扰素信号的严格调控。由于ISG15不存在于简单的真核生物中 在酵母和线虫等生物体中，它可能参与复杂有机体的特殊功能， 例如人和老鼠。我们的实验室是少数几个确定了关键酶、蛋白质的先驱小组之一 蛋白质ISG化的靶点和生化效应。此外，我们还生成了ISG15 E1 酶，Uba7，基因敲除和ISG15去结合酶，Usp18，基因敲除小鼠模型，缺乏 蛋白质ISG化和积累ISGylated蛋白质。ISG15表达上调 许多人类癌症。更重要的是，UBA7的表达与患者良好的生存相关 多种类型的人类癌症。在之前的资助期间，我们发现Uba7介导的 蛋白ISG化在干扰素相关肿瘤免疫微调中具有先前未知的功能 通过促进关键细胞因子和趋化因子的表达来实现串扰。基于目前的知识和我们的 初步数据显示，我们假设蛋白质ISG化参与了干扰素介导的染色质重塑， 癌细胞干细胞的限制和癌症治疗的疗效。为了验证这一假设，我们将执行 以下研究：目的1.检测干扰素介导的染色质重塑过程中的蛋白ISG化。 分析干扰素介导的肿瘤干细胞限制中的蛋白ISG化；目的3.研究肿瘤 阻断Usp18的ISG15去结合酶活性的治疗潜力。

Title: ISG15 and protein ISGylation in cancer Summary The long-term goal of this study is to understand the role of ISG15-related protein posttranslational modification (ISGylation, a ubiquitin-like modification) in cancer development and prognosis. In recent years our knowledge about type I interferon (IFN) signaling in cancer has expanded rapidly. It is now recognized that IFN plays important roles during cancer development and in the efficacy of cancer therapies. The bioactivity of IFN relies on the expression of many IFN-stimulated genes (ISGs). However, the functions of different ISGs associated with the effect of IFN in cancer remain largely unknown. ISG15 is one of the major ISGs. Its expression is strongly upregulated by IFN and by any cellular stress that promotes IFN production. Furthermore, most of the enzymes involved in protein ISGylation are also encoded by ISGs. Therefore, protein ISGylation is tightly regulated by IFN signaling. Since ISG15 is not found in simple eukaryotic organisms, such as yeast and nematodes, it is likely involved in specialized functions in complex organisms, such as human and mouse. Our lab is among a few pioneer groups that identified key enzymes, protein targets, and biochemical effects of protein ISGylation. Furthermore, we generated the ISG15 E1 enzyme,Uba7, knockout and ISG15 deconjugating enzyme, Usp18, knockout mouse models, which lack protein ISGylation and accumulate ISGylated proteins, respectively. ISG15 expression is upregulated in many human cancers. More importantly, expression of UBA7 is associated with favorable patient survival in multiple types of human cancer. During the previous funding period, we discovered that Uba7-mediated protein ISGylation had a previously unrecognized function in the fine tuning of IFN-related tumor-immune crosstalk by facilitating expression of key cytokines and chemokines. Based on current knowledge and our preliminary data, we hypothesize that protein ISGylation contributes to IFN-mediated chromatin remodeling, restriction of cancer cell stemness, and efficacy of cancer therapies. To test this hypothesis, we will perform the following studies: Aim 1. Examine protein ISGylation in IFN-mediated chromatin remodeling; Aim 2. Analyze protein ISGylation in IFN-mediated restriction of cancer stem cells; Aim 3. Investigate the cancer therapeutic potential of blocking the ISG15-deconjugating enzyme activity of Usp18.