Mechanism and Function of ISG15

ISG15的机制和功能

基本信息

批准号：
10297639
负责人：
JON HUIBREGTSE
金额：
$ 46.43万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10297639
关键词：
2019-nCoV Antiviral Agents Area Biochemical Biological Cell Surface Receptors Cells Communicable Diseases Coronavirus Cytotoxic T-Lymphocytes Development Directed Molecular Evolution Disease Enzymes Event Extracellular Space Family GTP-Binding Protein alpha Subunits, Gs Genetic Transcription Goals Homologous Gene Human ISG15 gene Immune Infection Innate Immune Response Integrins Interferon Type I Interferon Type II Interferons Interleukin-10 Interleukin-6 Intervention Lead Ligase Lysine Mediating Molecular Mus Mycobacterium Infections Mycobacterium tuberculosis Patients Play Principal Investigator Process Proteins Proteomics Role Signal Pathway Signal Transduction Signaling Protein Site Structure T-Lymphocyte Ubiquitin Ubiquitin Like Proteins Variant Vesicle Viral Viral Proteins Virus antimicrobial betacoronavirus cell type cytokine extracellular gene product human pathogen improved insight microbial novel pathogen pathogenic microbe pathogenic virus programs protein function response

项目摘要

SUMMARY Human ISG15 is a ubiquitin-like protein (Ubl) that functions in innate immune responses, and it is remarkable for possessing three distinct biochemical activities. As a ubiquitin-like modifier it is conjugated to hundreds of cellular and viral proteins. The E1, E2, E3, and de-conjugating enzymes for ISG15 (Ube1L/Uba7, UbcH8/Ube2L6, Herc5, and Usp18, respectively), are, like ISG15, induced at the transcriptional level by Type I interferon (IFN-α/β) signaling. A second function of ISG15 is as an extracellular signaling protein. ISG15 is released into the extracellular space from many cell types and signals to Natural Killer and T cells to secrete IFN-γ, which plays a major role in the response to pathogen infections. The cell surface receptor for extracellular SG15 is LFA-1, an immune cell-specific integrin. A third function of human ISG15 is that it negatively regulates Type I IFN signaling, as revealed by the Type I interferonopathy that occurs in some ISG15-deficient patients; this function of human ISG15 is not shared with mouse ISG15. A challenge in the field is to understand how the activities of ISG15 are regulated and temporally controlled and which activities are most closely associated with responses to specific pathogens, including Mycobacterium tuberculosis and SARS-CoV-2. To further our understanding of ISG15 in innate immune responses to these and other pathogens, this proposal will focus on the basis of substrate and lysine selectivity of the Herc5/Herc6 family of ISG15 ligases, the ISG15-induced signaling pathway downstream of LFA-1 that leads to cytokine secretion, and the mechanism by which ISG15 released into the extracellular space.

概括人ISG15是一种泛素样蛋白（UBL），可在先天免疫反应中起作用，它是具有三种不同的生化活动而引人注目。作为类似泛素的修饰符，它被共轭数百种细胞和病毒蛋白。 ISG15的E1，E2，E3和DE偶联酶（UBE1L/UBA7， UBCH8/UBE2L6，HERC5和USP18分别像ISG15一样，按I型在转录级别诱导干扰素（IFN-α/β）信号传导。 ISG15的第二个功能是细胞外信号蛋白。 ISG15是从许多细胞类型和信号到天然杀手和T细胞中释放到细胞外空间中 IFN-γ在对病原体感染的反应中起主要作用。细胞表面受体细胞外SG15是LFA-1，一种免疫细胞特异性整联蛋白。人ISG15的第三个功能是负调控I型IFN信号传导，如某些类型的I类干扰素揭示 ISG15缺陷患者；人ISG15的这种功能与鼠标ISG15不共享。在领域是要了解ISG15的活动如何受到监管和临时控制以及哪些活动与对特定病原体的反应最密切相关，包括结核分枝杆菌和 SARS-CoV-2。为了进一步了解ISG15在对这些和其他的先天免疫反应中病原体，该建议将重点介绍HERC5/HERC6家族的底物和赖氨酸的选择性 ISG15连接酶，ISG15诱导的LFA-1下游信号通路，导致细胞因子分泌，以及ISG15释放到细胞外空间的机制。