UBP43 in Hematopoiesis

描述（由申请人提供）：本研究的长期目标是了解ubp43 （usp18）在造血中的功能。造血是一个复杂的细胞增殖和分化过程。造血调节发生在多个层面，包括转录调节、信号转导和蛋白质修饰。我们克隆了一个去泛素化酶家族的新成员，命名为ubp43。进一步的研究表明，ubp43是一种蛋白酶，可以特异性地从蛋白质偶联物中去除泛素样蛋白ISG15。与磷酸化一样，isg酰化也是一种蛋白质修饰机制。然而，与磷酸化相比，对isg酰化的机制和后果的了解有限。干扰素强烈诱导ubp43表达。Ubp43缺陷小鼠对干扰素的造血反应存在根本差异。此外，ubp43缺陷造血细胞显著增强I型干扰素信号传导。最重要的是，ubp43在干扰素信号转导中具有解偶联酶活性依赖和独立的功能。这一提议验证了ubp43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isg酰化水平，在逆境条件下（如病毒和细菌感染以及基因毒性损伤）对造血至关重要的假设。在Specific Aim #1中提出的研究将表征ubp43酶在造血中的活性。在Specific Aim #2中提出的研究将探讨ubp43抑制I型干扰素信号传导的分子机制。在Specific Aim #3中提出的研究将研究ubp43在造血干细胞和祖细胞中的作用。提出的实验将解决ubp43在应激反应中造血过程中的基本问题，这可能为血液相关疾病的治疗提供有价值的见解。在对各种刺激的反应中，血细胞的形成在不同水平上受到严格调节。在病原体感染、干扰素治疗和其他压力下，Ubp43在血细胞中高度增加。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.