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.
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.
|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|
|Li, Yanchuan; Wang, Hui; Zhou, Xiaofei et al. (2016) Cell intrinsic role of NF-ÎºB-inducing kinase in regulating T cell-mediated immune and autoimmune responses. Sci Rep 6:22115|
|Hu, Hongbo; Sun, Shao-Cong (2016) Ubiquitin signaling in immune responses. Cell Res 26:457-83|
|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-ÎºB and mTORC1: Expanding roles of the CARMA1 complex. Mol Immunol 68:546-57|
|Romano, Simona; Xiao, Yichuan; Nakaya, Mako et al. (2015) FKBP51 employs both scaffold and isomerase functions to promote NF-ÎºB activation in melanoma. Nucleic Acids Res 43:6983-93|
|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|
|Zou, Qiang; Jin, Jin; Xiao, Yichuan et al. (2015) T cell development involves TRAF3IP3-mediated ERK signaling in the Golgi. J Exp Med 212:1323-36|
Showing the most recent 10 out of 35 publications