UBP43 in Hematopoiesis

描述（由申请方提供）：本研究的长期目标是了解ubp 43（usp 18）在造血中的功能。造血是细胞增殖和分化的复杂过程。造血调控发生在多个水平，包括转录调控，信号转导和蛋白质修饰。我们克隆了去泛素化酶家族的一个新成员，命名为ubp 43。进一步的研究表明，ubp 43是一种蛋白酶，其特异性地从蛋白缀合物中去除泛素样蛋白ISG 15。与磷酸化一样，ISGylation是蛋白质修饰的一种机制。然而，与磷酸化相反，对ISGylation的机制和后果只有有限的了解。干扰素强烈诱导ubp 43表达。Ubp 43缺陷型小鼠对干扰素的造血反应存在根本性差异。此外，ubp 43缺陷型造血细胞具有显著增强的I型干扰素信号传导。最重要的是，ubp 43在干扰素信号转导中具有解结合酶活性依赖性和非依赖性功能。该提案测试了这样的假设，即ubp 43通过与造血和JAK-STAT信号通路中的关键因子相互作用以及通过调节蛋白质ISGylation的水平，在应激条件下（例如病毒和细菌感染以及遗传毒性损伤）对造血至关重要。具体目标#1中提出的研究将表征造血中的ubp 43酶活性。具体目标#2中提出的研究将研究ubp 43抑制I型干扰素信号传导的分子机制。具体目标#3中提出的研究将研究ubp 43在造血干细胞和祖细胞中的作用。这些实验将解决有关ubp 43在应激反应中造血作用的基本问题，这可能为血液相关疾病的治疗提供有价值的见解。公共卫生相关性血细胞的形成在对各种刺激的反应中受到不同水平的严格调节。在病原体感染、干扰素治疗和其他应激时，血细胞中ubp 43高度增加。了解它在血细胞中的作用可能有助于开发新的疗法来治疗血细胞生成和功能的缺陷，如贫血和感染。

DESCRIPTION (provided by applicant): The long-term goal of this study is to understand the function of ubp43 (usp18) in hematopoiesis. Hematopoiesis is a complex process of cell proliferation and differentiation. Regulation of hematopoiesis occurs at multiple levels including transcriptional regulation, signal transduction, and protein modification. We cloned a novel member of the deubiquitinating enzyme family, termed ubp43. Further studies have demonstrated that ubp43 is a protease that specifically removes the ubiquitin like protein ISG15 from protein conjugates. Like phosphorylation, ISGylation is a mechanism of protein modification. However, in contrast to phosphorylation, only a limited understanding exists of the mechanisms and consequences of ISGylation. Interferons strongly induce ubp43 expression. Ubp43 deficient mice have fundamental differences in their hematopoietic response to interferons. Furthermore, ubp43 deficient hematopoietic cells have significantly enhanced type I interferon signaling. Most importantly, ubp43 has deconjugating enzyme activity dependent and independent functions in interferon signal transduction. This proposal tests the hypothesis that ubp43 is crucial for hematopoiesis under stress conditions, such as viral and bacterial infections and genotoxic insults, by interacting with critical factors in hematopoiesis and in the JAK-STAT signaling pathway and by regulating the level of protein ISGylation. The studies proposed in Specific Aim #1 will characterize ubp43 enzyme activity in hematopoiesis. The studies proposed in Specific Aim #2 will investigate the molecular mechanism of inhibition of type I interferon signaling by ubp43. The studies proposed in Specific Aim #3 will study the role of ubp43 in hematopoietic stem cells and progenitors. The experiments proposed will address fundamental questions about ubp43 in hematopoiesis during stress responses, which may provide valuable insight into the treatment of blood related diseases. PUBLIC HEALTH RELEVANCE Blood cell formation is tightly regulated at different levels in the response to various stimulations. Ubp43 is highly increased in blood cells upon pathogen infection, interferon treatment, and other stresses. Understand of its role in blood cells may help to develop novel therapies to treat defects in blood cell generation and function, such as anemia and infections.