Structural & Functional Studies of TLR/IL-1R Signaling

描述(申请人提供)：Toll样受体(TLRs)和促炎细胞因子受体IL-1和IL-18在其细胞内区域共享共同的TIR结构域，属于TLR/IL1-R超家族。TLR识别病原体相关分子模式(PAMP)以启动保护性免疫反应。这些受体的分子通路是复杂的，它们的失调与免疫系统内外的许多人类疾病有关。这些受体的信号转导是通过与PAMPs和细胞因子结合时受体TIR结构域的近似来启动的。这导致了细胞内含有TIR的接头如MyD88、TIRAP/MAL、TRIF和TRAM的募集。MyD88对IL-1、IL-18和除TLR3以外的所有TLRs的信号反应至关重要。MyD88除了其C端TIR结构域外，还含有一个N端死亡结构域(DD)。MyD88通过DD与IRAKs相互作用，包括IRAK1、IRAK2、IRAK4和IRAK-M。IRAK-M的特点是N端有一个DD，C端有一个丝氨酸/苏氨酸(Ser)/苏氨酸(Thr)或类似蛋白的结构域。最终，随后的途径激活转录因子NF-kB、AP-1和IRF，从而引发抗病原体反应和炎症。尽管TLR/IL-1R信号系统具有重要的生物学意义，但现有的结构和机制信息有限。在这一应用中，我们建议组装膜-近端信号复合体，并阐明这种信号转导的分子基础。 公共卫生相关性：在适当的生理环境中参与TLR/IL-1R途径可启动保护性免疫反应的发展。然而，这一途径的复杂性也使其本身容易受到干扰和调节失调，导致其与许多人类疾病有关。例如，TIR适配器和IRAK的遗传突变或多态可能导致对感染极端敏感或对感染具有保护作用。该通路中的其他类型的失调导致免疫系统中的疾病，如炎症性疾病、自身免疫性疾病和过敏，以及免疫系统以外的疾病，如癌症、胰岛素抵抗、动脉粥样硬化和痛性神经病。

DESCRIPTION (provided by applicant): Toll-like receptors (TLRs) and receptors for pro-inflammatory cytokines IL-1 and IL-18 share a common TIR domain in their intracellular region and belong to the TLR/IL1-R superfamily. TLRs recognize pathogen-associated molecular patterns (PAMPs) to initiate protective immune responses. The molecular pathways for these receptors are complex and their dysregulation is associated with many human diseases both within and beyond the immune system. Signal transduction of these receptors is initiated by the approximation of the receptor TIR domains upon binding of PAMPs and cytokines. This leads to the recruitment of intracellular TIR- containing adaptors such as MyD88, TIRAP/Mal, TRIF and TRAM. MyD88 is critical for signaling responses of IL-1, IL-18, and all TLRs except TLR3. In addition to its C-terminal TIR domain, MyD88 contains an N-terminal death domain (DD). Through the DD, MyD88 interacts with IRAKs, including IRAK1, IRAK2, IRAK4 and IRAK-M, which are characterized by an N- terminal DD and a C-terminal Ser/Thr kinase or kinase-like domain. Eventually, the ensuing pathway activates transcription factors NF-kB, AP-1, and IRFs to elicit anti-pathogen responses and inflammation. Despite the biological importance of the TLR/IL-1R signaling system, limited structural and mechanistic information is available. In this application, we propose to assemble the membrane- proximal signaling complexes and to elucidate the molecular basis of this signal transduction. PUBLIC HEALTH RELEVANCE: Engagement of the TLR/IL-1R pathway in appropriate physiological contexts initiates the development of protective immune responses. However, the complexity of this pathway also renders itself susceptible to interruption and dysregulation, leading to its association with many human diseases. For example, inherited mutations or polymorphisms in TIR-adapters and IRAKs may cause either extreme sensitivity to or protection against infections. Other types of dysregulation in the pathway contribute to both diseases in the immune system such as inflammatory disorders, autoimmune diseases and allergy, and diseases beyond the immune system such as cancer, insulin resistance, atherosclerosis, and painful neuropathy.