Our long-term goal is to study the mechanisms of protein ubiquitination in the regulation of immune responses. Allergic asthma is a chronic inflammatory disease of the airways featured by the elevated serum immunoglogulin E (IgE) concentrations, airway hyperresponsiveness, excessive airway mucus production, lung eosinophilia, and airway remodeling. Differentiation of CD4+ T cells into T helper type 2 (Th2) cells renders them to produce Th2 type cytokines to drive asthmatic pathogenesis. The Th2-mediated immune responses are counterbalanced by tolerogenic mechanisms that keep the excessive reaction under control. One of the tolerance mechanisms involves regulatory T cells (Tregs) that limit the allergic responses. Transforming growth factor (TGF)-? is critically involved in the generation and function of Tregs. Using both in vivo and in vitro model systems, we recently obtained preliminary data suggesting that the E3 ubiquitin ligase Itch plays an important role in the TGF-?-induced expression of Foxp3 and Treg- mediated proliferative inhibition. The new preliminary data allow us to formulate a hypothesis that the E3 ubiquitin ligase Itch is an important regulator in TGF-? signaling, which is linked to TGF-?-induced Treg generation. Such regulation of T cell function underlies the mechanistic involvement of Itch in the development of Th2-mediated allergic responses. We plan to test this hypothesis by proposing detailed experiments to elucidate the intracellular signaling pathways modulated by Itch-induced protein ubiquitination, with a combination of both genetic and biochemical approaches. Such studies will help to design novel therapeutic interventions for allergic diseases.

Public Health Relevance

Mechanisms of protein ubiquitination in regulating airway inflammation Narrative Asthma is on the rise in both industrialized and developing countries, which affects over 20 million people in the US alone. Allergic asthma is a chronic inflammatory disease of the airways. Differentiation of CD4+ T cells into T helper type 2 (Th2) cells renders them to produce cytokines, which are critical to drive asthmatic pathogenesis. This proposal is to study the regulatory mechanisms to control excessive T cell activation. The knowledge gained from the proposed research will help design new therapeutic approaches for human allergic diseases.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Dong, Gang
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La Jolla Institute
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Park, Yoon; Jin, Hyung-Seung; Lopez, Justine et al. (2016) SHARPIN controls regulatory T cells by negatively modulating the T cell antigen receptor complex. Nat Immunol 17:286-96
Lee, Jee H; Elly, Chris; Park, Yoon et al. (2015) E3 Ubiquitin Ligase VHL Regulates Hypoxia-Inducible Factor-1? to Maintain Regulatory T Cell Stability and Suppressive Capacity. Immunity 42:1062-74
Aki, Daisuke; Zhang, Wen; Liu, Yun-Cai (2015) The E3 ligase Itch in immune regulation and beyond. Immunol Rev 266:6-26
Park, Yoon; Jin, Hyung-seung; Aki, Daisuke et al. (2014) The ubiquitin system in immune regulation. Adv Immunol 124:17-66
Xiao, Nengming; Eto, Danelle; Elly, Chris et al. (2014) The E3 ubiquitin ligase Itch is required for the differentiation of follicular helper T cells. Nat Immunol 15:657-66
Jin, Hyung-seung; Park, Yoon; Elly, Chris et al. (2013) Itch expression by Treg cells controls Th2 inflammatory responses. J Clin Invest 123:4923-34
Park, Yoon; Jin, Hyung-seung; Liu, Yun-Cai (2013) Regulation of T cell function by the ubiquitin-specific protease USP9X via modulating the Carma1-Bcl10-Malt1 complex. Proc Natl Acad Sci U S A 110:9433-8
Jin, Hyung-seung; Liao, Lujian; Park, Yoon et al. (2013) Neddylation pathway regulates T-cell function by targeting an adaptor protein Shc and a protein kinase Erk signaling. Proc Natl Acad Sci U S A 110:624-9
Su, Jin; Liu, Yun-Cai (2010) Foxp3 positive regulatory T cells: a functional regulation by the E3 ubiquitin ligase Itch. Semin Immunopathol 32:149-56
Huang, Haining; Jeon, Myung-Shin; Liao, Lujian et al. (2010) K33-linked polyubiquitination of T cell receptor-zeta regulates proteolysis-independent T cell signaling. Immunity 33:60-70

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