The NF-?B family of transcription factors regulates diverse biological processes, including immune and inflammatory responses. NF-?B activation involves two major pathways: the canonical and noncanonical pathways. A central step in the noncanonical pathway is ubiquitin-dependent processing of the NF-?B2 precursor protein p100, which generates mature NF-?B2 p52 and cause nuclear translocation of the p100- sequestered noncanonical NF-?B members, p52 and RelB. During the previous funding cycles, the PI's laboratory has made pivotal contributions to the advancement of this relatively new field, including discovery of NIK as a central signaling component and identification of TRAF3 as a primary negative regulator that controls the fate of NIK. It is now known that TRAF3 functions as the substrate binding subunit of a NIK-specific E3 ubiquitin ligase complex, TRAF3-TRAF2-cIAP. Despite these progresses, our knowledge on noncanonical NF- ?B signaling is still quite limited. In particular, only few regulators of this pathway have been characterized, and the function of noncanonical NF-?B in different types of immune cells is poorly defined. The overall objective of this continuation application is to characterize novel regulators and functions of the noncanonical NF-?B pathway. The proposed studies are based on innovative preliminary data from the PI's laboratory. Using newly generated NIK-conditional KO mice, we demonstrated a dendritic cell (DC)- specific function of noncanonical NF-?B in regulating mucosal immunity and obtained important clues to the underlying mechanism. To identify novel regulators of the noncanonical NF-?B pathway, we employed a recently developed approach, BioID, to screen for proteins interacting with major components of this pathway. After extensive characterizations, we have identified a TRAF3-binding protein, TFG, and a p100-binding protein, Otub1, which are critically involved in noncanonical NF-?B regulation. TFG is crucial for preventing abnormal NIK accumulation, whereas Otub1 is a deubiquitinase (DUB) that inhibits p100 ubiquitination and processing. Our gene knockdown and KO mouse studies suggest important functions of TFG and Otub1 in immune regulation. These innovative findings form a solid foundation for this continuation application. To accomplish our overall objective, we will (1) elucidate the mechanism by which noncanonical NF-?B functions in DCs to regulate mucosal immunity; (2) characterize novel factors that regulate noncanonical NF-?B signaling; and (3) investigate the immunoregulatory functions of novel noncanonical NF-?B regulators. The PI's laboratory pioneered the discovery of noncanonical NF-?B pathway and has been in a leading position in this area. During the previous funding cycles, we have made seminal discoveries that have been instrumental for the advancement of the filed. We believe that the proposed studies will once again lead to high-impact findings that substantially advance the field. With our extensive experience and the innovative preliminary data, we are in a unique position to carry out the proposed studies.

Public Health Relevance

Narative The noncanonical (or atypical) NF-?B pathway regulates important immune functions and, when deregulated, is associated with autoimmunity, inflammation, and lymphoid malignancies. This research project focuses on the molecular mechanisms that control noncanonical NF-?B activation and will provide highly innovative knowledge that facilitates the development of new and effective immune therapies.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Zhao, Xiaoli
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
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
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
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:
Xiao, Yichuan; Zou, Qiang; Xie, Xiaoping et al. (2017) The kinase TBK1 functions in dendritic cells to regulate T cell homeostasis, autoimmunity, and antitumor immunity. J Exp Med 214:1493-1507
Wang, Bin; Jie, Zuliang; Joo, Donghyun et al. (2017) TRAF2 and OTUD7B govern a ubiquitin-dependent switch that regulates mTORC2 signalling. Nature 545:365-369
Li, Yanchuan; Wang, Hui; Zhou, Xiaofei et al. (2016) Cell intrinsic role of NF-?B-inducing kinase in regulating T cell-mediated immune and autoimmune responses. Sci Rep 6:22115

Showing the most recent 10 out of 45 publications