Ubiquitination has emerged as a pivotal mechanism that regulates signal transduction in the immune system. Deregulated ubiquitination events are associated with severe immunological disorders, such as autoimmunity and chronic inflammation. A critical component of the ubiquitination system is E3 ubiquitin ligase, a superfamily (more than 600 members) of enzymes that confer specificity of ubiquitination by recognizing substrates. Since each E3 targets a small number of proteins for ubiquitination, characterization of the physiological targets of specific E3s represents a challenging and highly significant task. This information is critical for rational design of therapeutic approaches. The long-range goal of this project is to understand the immunoregulatory functions of a newly identified family of E3 ubiquitin ligases, Peli (also called Pellino). Peli proteins conjugate both lysine (K) 63- and K48-linked polyubiquitin chains, although their in vivo biological functions remains poorly understood. By gene targeting, our preliminary studies and recently published work revealed a critical, and seemingly complex, role for Peli1 in the regulation of immune receptor signaling and autoimmunity. Peli1 negatively regulates T-cell activation and maintains T-cell tolerance, and Peli1 deficiency causes systemic autoimmune symptoms. Paradoxically, the Peli1 knockout (KO) mice are refractory to the induction of experimental autoimmune encephalomyelitis (EAE), an organ-specific autoimmune disease of the central nervous system (CNS). Interestingly, although the Peli1 KO mice have hyper-production of inflammatory T cells in the peripheral lymphoid organs, these immune cells failed to migrate to the CNS. We have obtained genetic evidence that Peli1 is required for innate immune receptor signaling and induction of proinflammatory cytokines and chemokines in the CNS-resident microglial cells. These innovative findings demonstrate a pivotal and paradoxical role for Peli1 in the regulation of T-cell activation and CNS innate immune receptor signaling. Elucidation of the underlying mechanism is highly important for therapeutic approaches. Thus, the overall objective of this grant application is to understand how Peli1 exerts its immunoregulatory functions. Our hypothesis is that Peli1 targets different signaling factors for ubiquitination, thereby regulating both innate immune cell activation and T-cell tolerance. To achieve our overall objective, we will (1) examine how Peli1 regulates T-cell activation and tolerance;(2) examine how Peli1 regulates innate immune receptor signaling and CNS inflammation;and (3) elucidate the biochemical mechanisms regulating the activation and function of Peli1.

Public Health Relevance

Protein ubiquitination has emerged as a pivotal mechanism that regulates signal transduction involved in immune response and inflammation. Deregulated ubiquitination events are associated with severe immunological disorders, such as autoimmunity and chronic inflammation. This research project focuses on the molecular mechanisms underlying the immunoregulatory functions of a newly identified E3, Peli1, and will provide highly innovative knowledge that facilitates the development of immune therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI104519-01
Application #
8469642
Study Section
Special Emphasis Panel (ZRG1-CB-F (03))
Program Officer
Esch, Thomas R
Project Start
2013-05-15
Project End
2018-04-30
Budget Start
2013-05-15
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$371,300
Indirect Cost
$136,300
Name
University of Texas MD Anderson Cancer Center
Department
Microbiology/Immun/Virology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Hu, Hongbo; Sun, Shao-Cong (2016) Ubiquitin signaling in immune responses. Cell Res 26:457-83
Hu, Hongbo; Wang, Hui; Xiao, Yichuan et al. (2016) Otud7b facilitates T cell activation and inflammatory responses by regulating Zap70 ubiquitination. J Exp Med 213:399-414
Jin, Jin; Xie, Xiaoping; Xiao, Yichuan et al. (2016) Epigenetic regulation of the expression of Il12 and Il23 and autoimmune inflammation by the deubiquitinase Trabid. Nat Immunol 17:259-68
Lereim, Ragnhild Reehorst; Oveland, Eystein; Xiao, Yichuan et al. (2016) The Brain Proteome of the Ubiquitin Ligase Peli1 Knock-Out Mouse during Experimental Autoimmune Encephalomyelitis. J Proteomics Bioinform 9:209-219
Xiao, Yichuan; Jin, Jin; Zou, Qiang et al. (2015) Peli1 negatively regulates type I interferon induction and antiviral immunity in the CNS. Cell Biosci 5:34
Yang, Xiao-Dong; Sun, Shao-Cong (2015) Targeting signaling factors for degradation, an emerging mechanism for TRAF functions. Immunol Rev 266:56-71
Jin, Jin; Xiao, Yichuan; Hu, Hongbo et al. (2015) Proinflammatory TLR signalling is regulated by a TRAF2-dependent proteolysis mechanism in macrophages. Nat Commun 6:5930
Shi, Jian-hong; Sun, Shao-Cong (2015) TCR signaling to NF-κB and mTORC1: Expanding roles of the CARMA1 complex. Mol Immunol 68:546-57
Chang, Jae-Hoon; Hu, Hongbo; Sun, Shao-Cong (2015) Survival and maintenance of regulatory T cells require the kinase TAK1. Cell Mol Immunol 12:572-9
Yu, Jiayi; Zhou, Xiaofei; Chang, Mikyoung et al. (2015) Regulation of T-cell activation and migration by the kinase TBK1 during neuroinflammation. Nat Commun 6:6074

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