ISG15 and Protein ISGylation in Cancer

癌症中的 ISG15 和蛋白质 ISG 化

• 批准号: 10590733
• 负责人: DONG-ER ZHANG
• 金额: $ 40.51万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590733
• 关键词: Biochemical; Biopsy; Breast Cancer Cell; CD8-Positive T-Lymphocytes; CXCL9 gene; CXCR3 gene; Cancer cell line; Cell Line; Cellular Stress; Chromatin; Chronic; Clinical Research; Complex; Cytokine Gene; Data; Development; Enzymes; Funding; Gene Expression; Genes; Genomic approach; Goals; Heterogeneity; Human; ISG15 gene; Immune; Immunocompetent; Immunotherapy; Infiltration; Inflammatory; Interferon Activation; Interferon Type I; Interferons; Knock-in; Knock-out; Knockout Mice; Knowledge; Ligands; Link; Malignant Neoplasms; Mammary Neoplasms; Mediating; Metastatic Neoplasm to the Lung; Modification; Molecular; Mus; Nematoda; Neoplasm Circulating Cells; Neoplasm Metastasis; Organism; Patients; Play; Population; Post-Translational Protein Processing; Production; Prognosis; Property; Proteins; Reporting; Response Elements; Role; STAT1 gene; STAT2 gene; Signal Transduction; Stimulus; T cell infiltration; TLR4 gene; Testing; Therapeutic; Transcriptional Activation; Tumor Cell Invasion; Tumor Immunity; Tumor Promotion; Tumor Suppression; Ubiquitin; Ubiquitin Like Proteins; Yeasts; angiogenesis; anti-PD-1; cancer cell; cancer stem cell; cancer therapy; cancer type; chemokine; chromatin remodeling; cytokine; effective therapy; enzyme activity; epithelial to mesenchymal transition; human disease; inhibitor; insight; malignant breast neoplasm; melanoma; mouse model; mutant; neoplastic cell; novel; response; single-cell RNA sequencing; stem cell function; stem-like cell; stemness; transcriptome sequencing; treatment response; tumor

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.

标题：癌症中的 ISG15 和蛋白质 ISGylation 概括 本研究的长期目标是了解 ISG15 相关蛋白翻译后的作用 癌症发展和预后中的修饰（ISGylation，一种泛素样修饰）。最近几年 我们对癌症中 I 型干扰素 (IFN) 信号传导的了解迅速扩展。现在已经被认可了 干扰素在癌症发展和癌症治疗功效中发挥着重要作用。这 IFN 的生物活性依赖于许多 IFN 刺激基因 (ISG) 的表达。然而，功能 与 IFN 在癌症中的作用相关的不同 ISG 仍然很大程度上未知。 ISG15是主要的之一 ISG。 IFN 和任何促进 IFN 产生的细胞应激都会强烈上调其表达。 此外，大多数参与蛋白质ISG化的酶也是由ISG编码的。所以， 蛋白质 ISGylation 受到 IFN 信号传导的严格调控。由于ISG15在简单的真核生物中没有发现 生物体，例如酵母和线虫，它可能参与复杂生物体的特殊功能， 比如人类和老鼠。我们的实验室是鉴定关键酶、蛋白质的少数先驱团体之一 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，敲除和 ISG15 解偶联酶，Usp18，敲除小鼠模型，缺乏 分别是蛋白质ISGylation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率相关。 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 蛋白质ISG化在IFN相关肿瘤免疫的微调中具有以前未被认识到的功能 通过促进关键细胞因子和趋化因子的表达来进行串扰。根据现有知识和我们的 初步数据，我们假设蛋白质 ISGylation 有助于 IFN 介导的染色质重塑， 癌细胞干性的限制和癌症治疗的功效。为了检验这个假设，我们将执行 以下研究： 目标 1. 检查 IFN 介导的染色质重塑中的蛋白质 ISGylation；目标2。 分析 IFN 介导的癌症干细胞限制中的蛋白质 ISGylation；目标 3. 研究癌症 阻断 Usp18 的 ISG15 解偶联酶活性的治疗潜力。

项目成果

Murine Herc6 Plays a Critical Role in Protein ISGylation In Vivo and Has an ISGylation-Independent Function in Seminal Vesicles.

鼠 Herc6 在体内蛋白质 ISG 化中发挥关键作用，并且在精囊中具有独立于 ISG 化的功能。

• DOI: 10.1089/jir.2014.0113
• 发表时间: 2015-05-05
• 期刊: Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research
• 作者: K. Arimoto;Takayuki Hishiki;H. Kiyonari;T. Abe;C. Cheng;Ming Yan;Jun;M. Futakuchi;H. Tsuda;Yoshiki Murakami;Hideyuki Suzuki;Dong;K. Shimotohno
• 通讯作者: K. Shimotohno

STAT2 is an essential adaptor in USP18-mediated suppression of type I interferon signaling.

STAT2 是 USP18 介导的 I 型干扰素信号传导抑制中的重要接头。

• 发表时间: 2017
• 影响因子: 16.8
• 作者: Arimoto, Kei;Löchte, Sara;Stoner, Samuel A;Burkart, Christoph;Zhang, Yue;Miyauchi, Sayuri;Wilmes, Stephan;Fan, Jun;Heinisch, Jürgen J;Li, Zhi;Yan, Ming;Pellegrini, Sandra;Colland, Frédéric;Piehler, Jacob;Zhang, Dong
• 通讯作者: Zhang, Dong

Cell-cycle-gated feedback control mediates desensitization to interferon stimulation.

细胞周期门控反馈控制介导对干扰素刺激的脱敏。

• 发表时间: 2020
• 影响因子: 7.7
• 作者: Mudla, Anusorn;Jiang, Yanfei;Arimoto, Kei;Xu, Bingxian;Rajesh, Adarsh;Ryan, Andy P;Wang, Wei;Daugherty, Matthew D;Zhang, Dong;Hao, Nan
• 通讯作者: Hao, Nan

Type I IFN induces protein ISGylation to enhance cytokine expression and augments colonic inflammation.

I 型 IFN 诱导蛋白质 ISGylation，以增强细胞因子表达并加剧结肠炎症。

• 发表时间: 2015-11-17
• 影响因子: 11.1
• 作者: Fan, Jun;Miyauchi;Arimoto, Kei;Liu, Dan;Yan, Ming;Liu, Chang;Győrffy, Balázs;Zhang, Dong
• 通讯作者: Zhang, Dong

The probacterial effect of type I interferon signaling requires its own negative regulator USP18.

I 型干扰素信号传导的益菌作用需要其自身的负调节因子 USP18。

• 发表时间: 2018
• 影响因子: 24.8
• 作者: Shaabani, Namir;Honke, Nadine;Nguyen, Nhan;Huang, Zhe;Arimoto, Kei;Lazar, Daniel;Loe, Taylor K;Lang, Karl S;Prinz, Marco;Knobeloch, Klaus;Zhang, Dong;Teijaro, John R
• 通讯作者: Teijaro, John R