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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Esch, Thomas R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas MD Anderson Cancer Center
United States
Zip Code
Zhu, Lele; Xie, Xiaoping; Zhang, Lingyun et al. (2018) TBK-binding protein 1 regulates IL-15-induced autophagy and NKT cell survival. Nat Commun 9:2812
Liu, Junli; Huang, Xinfang; Hao, Shumeng et al. (2018) Peli1 negatively regulates noncanonical NF-?B signaling to restrain systemic lupus erythematosus. Nat Commun 9:1136
Jie, Zuliang; Yang, Jin-Young; Gu, Meidi et al. (2018) NIK signaling axis regulates dendritic cell function in intestinal immunity and homeostasis. Nat Immunol 19:1224-1235
Yang, Jie; Zhang, Siya; Zhang, Lingyun et al. (2018) Lymphatic endothelial cells regulate B-cell homing to lymph nodes via a NIK-dependent mechanism. Cell Mol Immunol :
Shi, Jian-Hong; Sun, Shao-Cong (2018) Tumor Necrosis Factor Receptor-Associated Factor Regulation of Nuclear Factor ?B and Mitogen-Activated Protein Kinase Pathways. Front Immunol 9:1849
Shi, Jian-Hong; Xie, Xiaoping; Sun, Shao-Cong (2018) TBK1 as a regulator of autoimmunity and antitumor immunity. Cell Mol Immunol 15:743-745
Sun, Shao-Cong (2017) The non-canonical NF-?B pathway in immunity and inflammation. Nat Rev Immunol 17:545-558
Liu, Ting; Zhang, Lingyun; Joo, Donghyun et al. (2017) NF-?B signaling in inflammation. Signal Transduct Target Ther 2:
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
Hu, Hongbo; Sun, Shao-Cong (2016) Ubiquitin signaling in immune responses. Cell Res 26:457-83

Showing the most recent 10 out of 26 publications