Mechanism and Function of ISG15 Conjugation

ISG15缀合的机制和功能

• 批准号: 8258706
• 负责人: JON HUIBREGTSE
• 金额: $ 33.19万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8258706
• 关键词: Address; Adverse effects; Amino Acid Sequence; Antiviral Agents; Biochemical; Capsid; Capsid Proteins; Cells; Clinical; Code; DNA Packaging; Data; Disease; Dominant-Negative Mutation; Enzymes; Gene Delivery; Goals; Hepatitis B; Hepatitis C; Human; Human Papillomavirus; Human Virus; Immune response; In Vitro; Individual; Infectious Agent; Influenza; Interferons; Ligase; Malignant Neoplasms; Maps; Mediating; Modeling; Modification; Molecular; Multiple Sclerosis; Oncolytic viruses; Papillomavirus; Pathway interactions; Peptide Sequence Determination; Predisposition; Principal Investigator; Process; Proteins; Proteomics; Reagent; Retroviridae; Ribosomes; Site; Specificity; Structural Protein; Structure; System; Testing; Therapeutic Effect; Translating; Translations; Ubiquitin Like Proteins; Ubiquitination; Viral; Viral Physiology; Viral Proteins; Viral Structural Proteins; Virion; Virus; Virus Diseases; Virus Replication; Work; arm; base; cancer type; improved; interferon therapy; particle; polypeptide; programs; public health relevance; receptor; reconstitution; response; vector

DESCRIPTION (provided by applicant): The type 1-interferon (IFN) response is the first line of defense against viral infections. Hundreds of proteins are induced in IFN-stimulated cells, and these proteins mediate a wide spectrum of anti-viral effects. ISG15 was one of the first IFN-induced proteins to be identified and the first ubiquitin-like protein (Ubl) to be discovered, however its biochemical function and the basis of its antiviral activities have remained largely uncharacterized for many years. ISG15 has anti-viral activity against a wide range of human viruses, including influenza, retroviruses, sindbis, ebola, and the ability of ISG15 to be conjugated to other proteins is likely to be essential for its anti-viral activity in all cases. ISG15 is conjugated to hundreds of cellular proteins in IFN-stimulated cells, and a single IFN-induced ligase, Herc5, mediates conjugation to nearly all of these target proteins. Based on extensive preliminary data, we hypothesize that Herc5 is ribosome-associated and ISGylates proteins in a co-translational manner, with little target protein specificity. We further hypothesize that in the context of an interferon response, newly translated viral proteins, rather than cellular proteins are the primary targets of this system, and that ISGylation is an attempt to inactivate the function of viral proteins. The aims of this proposal will test both of these hypotheses. The interferon response is a mutli-faceted defensive shield that protects cells against a wide range of infectious agents, yet only a small number of IFN-induced proteins have been characterized in molecular detail. In addition, interferon is used therapeutically in treating viral infections (e.g., hepatitis B and C and papillomaviruses), as well as certain types of cancers and multiple sclerosis, yet it is not known which IFN-induced proteins mediate useful therapeutic effects and which mediate the notorious side effects of these therapies. A further understanding of the mechanism and function of ISG15 conjugation will present opportunities for either up- or down-modulating ISGylation activity in these clinical settings. PUBLIC HEALTH RELEVANCE: ISG15 conjugation is now recognized to be an important aspect of the innate immune response against a wide range of human viral infections, and interferon therapies are approved for many disease states. It is essential to characterize the many facets of the interferon response system, including the ISG15 pathway, in order to improve and modulate anti-viral and interferon therapies.

描述（由申请人提供）：1类交换剂（IFN）反应是针对病毒感染的第一道防线。在IFN刺激的细胞中诱导了数百种蛋白质，这些蛋白质介导了广泛的抗病毒作用。 ISG15是要鉴定的第一个IFN诱导的蛋白质之一，并且是第一个被发现的泛素样蛋白（UBL），但是其生化功能及其抗病毒活性的基础在很大程度上保持了很多年。 ISG15具有针对多种人类病毒的抗病毒活性，包括流感，逆转录病毒，信德氏菌，埃博拉病毒，ISG15与其他蛋白质共轭的能力在所有情况下可能对其抗病毒活性至关重要。 ISG15与IFN刺激细胞中数百种细胞蛋白结合，单个IFN诱导的连接酶HERC5介导了几乎所有这些靶蛋白的共轭。基于广泛的初步数据，我们假设HERC5是核糖体相关的，并且以核翻译方式与靶标的蛋白质相关，而靶蛋白特异性很少。我们进一步假设，在干扰素反应的背景下，新翻译的病毒蛋白，而不是细胞蛋白是该系统的主要靶标，而Isgylation是试图使病毒蛋白功能失活的尝试。该提案的目的将检验这两个假设。 干扰素反应是一种针对MUTLI的防御屏蔽层，可保护细胞免受广泛的感染剂的影响，但仅以分子细节来表征少数IFN诱导的蛋白质。此外，干扰素用于治疗病毒感染（例如乙型肝炎和C和乳头瘤病毒），以及某些类型的癌症和多发性硬化症，但尚不清楚IFN诱导的蛋白质介导了有用的治疗效果，哪些介导了这些疗法的著名副作用。对ISG15共轭的机制和功能的进一步理解将为这些临床环境中的上调节或下调的ISGyLation活动提供机会。 公共卫生相关性：ISG15结合现在被认为是针对广泛的人类病毒感染的先天免疫反应的重要方面，并且批准了许多疾病状态的干扰素疗法。为了改善和调节抗病毒和干扰素疗法，要表征包括ISG15途径在内的干扰素反应系统的许多方面至关重要。