Signal transduction from toll-like receptors (TLRs) mediates innate immune cell activation in host defense against infections; however, deregulated TLR signaling also contributes to the development of inflammatory diseases. The long-range goal of this research project is to understand the molecular mechanisms regulating TLR signaling in macrophages, a major type of innate immune cells involved in the regulation of immune responses, inflammation, as well as tumor microenvironment. During the previous funding cycles, the PI's laboratory has made seminal discoveries in this area. Moreover, we have generated a large body of innovative preliminary data that form a solid foundation for this continuation application. In particular, our preliminary studies identified a novel TLR signaling mediator, Zranb1 (also called Trabid). Zranb1 is a deubiquitinase with poorly defined physiological functions due to the lack of an animal model. Using newly generated Zranb1 conditional KO mice, we found that Zranb1 deficiency in macrophages specifically attenuates TLR-stimulated expression of a subset of proinflammatory cytokines, including IL-12 and IL-23. We have obtained preliminary evidence that Zranb1 regulates the fate of c-Rel, a transcription factor involved in IL-12/IL-23 gene induction. Along the same line, our preliminary studies led to the unexpected observation that a TRAF family member, TRAF2, serves as a pivotal negative regulator of the proinflammatory axis of TLR signaling. TRAF2 aberrant expression is associated with human inflammatory bowel disease (IBD), but it has been unclear whether TRAF2 positively or negatively regulates colon inflammation. By generating myeloid cell-conditional Traf2 KO (Traf2-MKO) mice, we demonstrated that TRAF2 ablation greatly promotes TLR-stimulated proinflammatory cytokine expression in macrophages and sensitizes mice for colitis induction in an animal model of IBD. We further showed that TRAF2 deficiency in macrophages leads to marked accumulation of c-Rel and IRF5, major transcription factors mediating induction of proinflammatory cytokines. Interestingly, our data suggest the regulation of c-Rel and IRF5 by a novel ubiquitin/proteasome-dependent mechanism relying on both TRAF2 and a related TRAF member, TRAF3. Collectively, these findings establish TRAF2 and Zranb1 as pivotal regulators of TLR signaling and highlight a novel signaling mechanism. Our hypothesis is that TRAF2 and Zranb1 regulate the proinfammatory axis of TLR signaling through controlling the fate of important signaling molecules, including c-Rel and IRF5. To test this hypothesis, we will (1) elucidate the mechanism by which TRAF2 regulates TLR signaling in macrophages; (2) define the molecular mechanism by which Zranb1 mediates TLR signaling; and (3) investigate the in vivo pathophysiological functions of TRAF2 and Zranb1 in myeloid cells. We believe that the proposed project addresses a unique and novel aspect of TLR signaling and will yield innovative results that substantially advance the field.

Public Health Relevance

Toll-like receptor (TLR) signaling mediates host defense against infections, but deregulated TLR signaling is linked to inflammatory diseases. The proposed project addresses innovative questions regarding the mechanism underlying TLR signaling and inflammation and will lead to high-impact findings with therapeutic implications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI057555-15
Application #
9407002
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Jiang, Chao
Project Start
2004-03-01
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
15
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Microbiology/Immun/Virology
Type
Hospitals
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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Hu, Hongbo; Sun, Shao-Cong (2016) Ubiquitin signaling in immune responses. Cell Res 26:457-83
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
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
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
Shi, Jian-hong; Sun, Shao-Cong (2015) TCR signaling to NF-?B and mTORC1: Expanding roles of the CARMA1 complex. Mol Immunol 68:546-57
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
Yang, Xiao-Dong; Sun, Shao-Cong (2015) Targeting signaling factors for degradation, an emerging mechanism for TRAF functions. Immunol Rev 266:56-71

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