Recognition of microbes by Toll-like receptors (TLRs) triggers the induction of proinflammatory cytokines and other immune mediators, which serves as an important innate immune mechanism against infections. However, uncontrolled secretion of inflammatory mediators causes chronic inflammatory diseases or even a devastating acute illness, septic shock. The long-range goal of this project is to dissect the signaling pathways involved in TLR-mediated induction of inflammatory mediators. This knowledge is important for rational design of more effective anti-inflammatory therapies. Over the past few years, we have made seminal findings demonstrating a pivotal TLR signaling axis: the IKK/Tpl2 axis. IKK is known as a kinase that activates the transcription factor NF-(B by mediating phosphorylation and degradation of the NF-(B inhibitor I(B, whereas Tpl2 is a MAP3K that activates the MAP kinase ERK through phosphorylating the ERK kinase, MEK1. Interestingly, Tpl2 is sequestered by an I(B-like molecule, p105, and the activation of Tpl2 requires IKK-mediated p105 phopshorylation and degradation. Thus, the IKK/Tpl2 signaling axis controls two major TLR pathways, the NF-(B and ERK pathways. The overall objective of this continuation application is to understand how IKK regulates Tpl2 and how the IKK/Tpl2 signaling axis is activated by upstream TLR signals. The proposed project is based on strong preliminary data from our laboratory. In particular, our studies have revealed the involvement of IKK/Tpl2 functional interplay and novel signaling factors in TLR-stimulated p105 degradation and Tpl2 activation. We have further shown that in addition to mediating Tpl2 activation, IKK controls the fate of activated Tpl2, a function that may prevent prolonged Tpl2 activation. Additionally, we made significant progress toward understanding the mechanism that connects the IKK/Tpl2 axis to upstream TLR signals. Our genetic evidence suggest that a recently identified E3 ubiquitin ligase, Pellino1, mediates IKK/Tpl2 activation by specific TLRs. Together, these innovative preliminary results form a solid foundation for the studies proposed in this application. We will perform three specific aims to accomplish our overall objective. (1) Examine the molecular mechanism of IKK- dependent Tpl2 activation. (2) Examine the role of IKK in regulating the fate of Tpl2. (3) Examine how the IKK/Tpl2 signaling axis is regulated by upstream TLR signals

Public Health Relevance

Toll-like receptors detect various microbial components and signal host cells to produce various inflammatory mediators that combat infection, however, prolonged or exacerbated production of inflammatory mediators can cause chronic or acute inflammatory diseases. The goal of this research project is to understand the molecular mechanism by which toll-like receptors transduce signals leading to the induction of host immune factors, which is important for rational design of more effective anti-inflammatory therapies.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Cellular Signaling and Regulatory Systems Study Section (CSRS)
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Palker, Thomas J
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University of Texas MD Anderson Cancer Center
Other Domestic Higher Education
United States
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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 :
Zhang, Huiyuan; Li, Haiyan S; Hillmer, Emily J et al. (2018) Genetic rescue of lineage-balanced blood cell production reveals a crucial role for STAT3 antiinflammatory activity in hematopoiesis. Proc Natl Acad Sci U S A 115:E2311-E2319
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:
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

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