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.
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.
|Arimoto, Kei-Ichiro; Löchte, Sara; Stoner, Samuel A et al. (2017) STAT2 is an essential adaptor in USP18-mediated suppression of type I interferon signaling. Nat Struct Mol Biol 24:279-289|
|Arimoto, Kei-ichiro; Hishiki, Takayuki; Kiyonari, Hiroshi et al. (2015) Murine Herc6 Plays a Critical Role in Protein ISGylation In Vivo and Has an ISGylation-Independent Function in Seminal Vesicles. J Interferon Cytokine Res 35:351-8|
|Arimoto, Kei-ichiro; Burkart, Christoph; Yan, Ming et al. (2014) Plakophilin-2 promotes tumor development by enhancing ligand-dependent and -independent epidermal growth factor receptor dimerization and activation. Mol Cell Biol 34:3843-54|
|Dauphinee, S M; Richer, E; Eva, M M et al. (2014) Contribution of increased ISG15, ISGylation and deregulated type I IFN signaling in Usp18 mutant mice during the course of bacterial infections. Genes Immun 15:282-92|
|Arimoto, Kei-Ichiro; Weng, Stephanie; Zhang, Dong-Er (2014) Plakophilin-2 induced EGFR phosphorylation: a focus on the intracellular activators of EGFR. Receptors Clin Investig 2:e485|
|Burkart, Christoph; Arimoto, Kei-ichiro; Tang, Tingdong et al. (2013) Usp18 deficient mammary epithelial cells create an antitumour environment driven by hypersensitivity to IFN-? and elevated secretion of Cxcl10. EMBO Mol Med 5:1035-50|
|Honke, Nadine; Shaabani, Namir; Zhang, Dong-Er et al. (2013) Usp18 driven enforced viral replication in dendritic cells contributes to break of immunological tolerance in autoimmune diabetes. PLoS Pathog 9:e1003650|
|Yim, Hwa Young; Yang, Young; Lim, Jong-Seok et al. (2012) The mitochondrial pathway and reactive oxygen species are critical contributors to interferon-?/?-mediated apoptosis in Ubp43-deficient hematopoietic cells. Biochem Biophys Res Commun 423:436-40|
|Honke, Nadine; Shaabani, Namir; Cadeddu, Giuseppe et al. (2012) Enforced viral replication activates adaptive immunity and is essential for the control of a cytopathic virus. Nat Immunol 13:51-7|
|Cong, Xiu-Li; Lo, Miao-Chia; Reuter, Brian A et al. (2012) Usp18 promotes conventional CD11b+ dendritic cell development. J Immunol 188:4776-81|
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