The NF-?B family of transcription factors regulates diverse biological processes, including immune response, inflammation, cell growth and survival. NF-?B activation involves two major pathways: the canonical and noncanonical pathways. Despite the extensive studies of the canonical pathway, the noncanonical pathway is still poorly understood. Recent studies, pioneered by the PI?s group, suggest that activation of the noncanonical NF-?B pathway involves degradation of an inhibitory protein, TRAF3, and stabilization of the NF-?B-inducing kinase (NIK). However, how these signaling events are negatively controlled is still unknown. This knowledge is highly significant, since deregulated activation of the noncanonical NF-?B pathway is associated with severe human diseases, including lymphoid disorders and cancer. The overall objective of this continuation application is to characterize the molecular mechanisms mediating the negative regulation of signal-induced noncanonical NF-?B signaling. The proposed studies are based on highly innovative preliminary data from our laboratory. In particular, we have identified two novel signaling factors the deubiquitinase Otud7b and the protein kinase TBK1, with pivotal roles in the negative regulation of noncanonical NF-?B signaling. Our data suggest that Otud7b and TBK1 may act in different signaling steps to prevent aberrant activation of noncanonical NF-?B. Using newly generated Otud7b knockout (KO) mice and TBK1 conditional KO mice, we have obtained evidence suggesting an important role for Otud7b and TBK1 in regulating antibody responses and maintaining lymphoid homeostasis in the intestine, an organ with dynamic host-microbiota interactions. Our central hypothesis is that Otud7b and TBK1 control the magnitude of signal-induced noncanonical NF-?B activation and, thereby, maintain normal immune homeostasis and responses. To address this hypothesis and accomplish our overall objective, we will (1) examine how the deubiquitinase Otud7b controls signal-induced TRAF3 degradation and noncanonical NF-?B activation;(2) elucidate the mechanism by which TBK1 regulates the fate of NIK and the magnitude of noncanonical NF-?B signaling;and (3) characterize the in vivo role of Otud7b and TBK1 in regulating noncanonical NF-?B signaling and immune functions. The PI?s laboratory pioneered the studies that led to the discovery of the noncanonical NF-?B pathway as well as to the elucidation of the mechanism underlying the steady-state noncanonical NF-?B regulation. We believe that the studies proposed in the current application will once again lead to a major advancement of the field, since they address the currently unknown mechanism that negatively controls signal-induced noncanonical NF-?B activation. In addition to the conceptual innovation, the newly generated Otud7b KO mice and TBK1 conditional KO mice serve as highly innovative models for studying the pathophysiology of noncanonical NF-?B signaling.

Public Health Relevance

The noncanonical (or atypical) NF-?B pathway is an important arm of the NF-?B signaling network that regulates important immune functions. Deregulated activation of this pathway is associated with autoimmunity, inflammation, and lymphoid malignancies;however, how the noncanonical NF-?B pathway is regulated remains largely unclear. 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM084459-11
Application #
8455764
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Gaillard, Shawn R
Project Start
2003-01-01
Project End
2016-11-30
Budget Start
2012-12-07
Budget End
2013-11-30
Support Year
11
Fiscal Year
2013
Total Cost
$316,000
Indirect Cost
$116,000
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
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
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 :
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
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

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