The IKK/Tpl2 axis of TLR signaling

描述(由申请人提供)：Toll样受体(TLRs)对微生物的识别可触发促炎细胞因子和其他免疫介质的诱导，这是对抗感染的重要先天免疫机制。然而，炎症介质的不受控制的分泌会导致慢性炎症性疾病，甚至是一种毁灭性的急性疾病，感染性休克。该项目的长期目标是剖析TLR介导的炎症介质诱导的信号通路。这些知识对于合理设计更有效的抗炎疗法非常重要。在过去的几年里，我们已经取得了开创性的发现，证明了一个关键的TLR信号轴：IKK/Tpl2轴。IKK被认为是一种通过介导转录因子NF-(B)的磷酸化和降解来激活转录因子NF-(B)的激酶，而Tpl2是一种MAP3K，通过磷酸化ERK激酶MEK1来激活MAP激酶ERK。有趣的是，Tpl2被I(类B)分子p105隔离，而Tpl2的激活需要IKK介导的p105磷酸化和降解。因此，IKK/Tpl2信号轴控制着两个主要的TLR通路，即NF-(B)和ERK通路。本继续应用的总体目标是了解IKK如何调节Tpl2，以及上游TLR信号如何激活IKK/Tpl2信号轴。拟议的项目是基于我们实验室提供的强大的初步数据。特别是，我们的研究揭示了IKK/Tpl2功能相互作用和新的信号因子参与TLR刺激的p105降解和Tpl2激活。我们进一步证明，除了介导Tpl2的激活外，ikk还控制激活的Tpl2的命运，这一功能可能阻止Tpl2的长时间激活。此外，我们在理解连接IKK/Tpl2轴和上游TLR信号的机制方面取得了重大进展。我们的遗传学证据表明，最近发现的E3泛素连接酶Pellino1通过特定的TLRs介导IKK/Tpl2的激活。总而言之，这些创新的初步结果为本申请中提出的研究奠定了坚实的基础。我们将落实三个具体目标，实现总目标。(1)研究IKK依赖的Tpl2激活的分子机制。(2)研究ikk在调控Tpl2命运中的作用。(3)研究上游TLR信号如何调节IKK/Tpl2信号轴 公共卫生相关性：Toll样受体检测各种微生物成分并向宿主细胞发送信号，以产生各种抗击感染的炎症介质，然而，长期或加剧炎症介质的产生可导致慢性或急性炎症性疾病。本研究的目的是了解Toll样受体转导信号从而诱导宿主免疫因子的分子机制，这对于合理设计更有效的抗炎治疗具有重要意义。

DESCRIPTION (provided by applicant): 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.