Structural Regulation of IRF3 Activation and Association with Co-activators of the IFN Beta Enhanceosome

项目总结 暴露在病毒中后，免疫系统会激活并迅速采取措施保护身体免受 一种蔓延的感染。我们对导致免疫激活的信号级联反应的理解 对病毒感染的治疗对于设计有效的治疗药物来规范这一过程至关重要。细胞表面和 胞质受体识别病原体特异性分子，如激活 干扰素调节因子3(IRF3)是免疫激活的主要调节因子。一旦激活，IRF3 促进干扰素β(干扰素β)的表达，这是抗病毒反应所必需的。尽管红外线3的S 在抗病毒反应中发挥积极作用，IRF3表达失调与多发性自身免疫有关 疾病。对干扰素β的严格调控对于减少对感染宿主的不受控制的炎症损害至关重要 同时清除感染。IRF3与ATF2/c-jun、p65/p50和IRF7一起形成了一个更高级的分子 被称为干扰素β增强体的复合体能够严格调控干扰素β的表达。虽然该规则的原则 激活irf3并诱导干扰素β表达的信号通路被建立，对 IRF3和干扰素β增强体组装的激活仍然很少。在这项提案中，我试图将 用X射线结晶学研究了IRF3活化的结构机理。那么，我将使用低温电子 显微镜观察促进IRF3与增强体p65相互作用的结构特征。 这些研究将提供对其他红外线受体如何被激活以及其他增强体如何被激活的见解 复合体聚集在一起。最重要的是，基于结构的分析IRF3的激活和与p65的组装 将为设计可直接靶向活化的小分子调节剂提供基础 分别抑制IRF3对病毒感染和自身免疫性疾病的反应。 好了！

PROJECT SUMMARY Following exposure to a virus, the immune system activates and takes rapid measures to protect the body from a spreading infection. Our understanding of the signaling cascade that leads to immuno-activation in response to viral infections is crucial for designing efficient therapeutic drugs that regulate this process. Cell surface and cytosolic receptors recognize pathogen-specific molecules such as viral nucleic acids that activate the interferon regulator factors 3 (IRF3), which is a master regulator of immune activation. Once activated, IRF3 promotes the expression of interferon β (IFNβ), which is essential for the antiviral response. Despite IRF3's active role in antiviral response, dysregulation in IRF3 expression has been implicated in multiple autoimmune diseases. Strict regulation of IFNβ is critical to minimize uncontrolled inflammation damage to infected hosts while clearing the infection. Together with ATF2/c-Jun, p65/p50, and IRF7, IRF3 form a higher order molecular complex called the IFNβ enhanceosome to strictly regulate IFNβ expression. While the principles of the signaling pathway that activates IRF3 and induces IFNβ expression are established, structural insights into the activation of IRF3 and IFNβ enhanceosome assembly remain scarce. In this proposal, I seek to characterize the structural mechanism of IRF3 activation by using X-ray crystallography. Then, I will use cryo-electron microscopy to characterize the structural features promoting IRF3 interactions with p65 at the enhanceosome. These studies will provide insights into how the other IRFs get activated and how other enhanceosome complexes assemble. Most importantly, structural-based analyses of IRF3 activation and assembly with p65 will provide a basis for designing small molecule modulators that can directly target the activation and suppression of IRF3 in response to viral infections and autoimmune diseases, respectively. !