SPOP负调控TLRs信号通路的分子机制研究

Toll-like receptors (TLRs) are pattern recognition receptors that are critically involved in host defense against microbial infections. Ligand binding by TLRs leads to the recruitment of TIR domain-containing adaptor proteins, such as myeloid differentiation primary-response gene 88 (MyD88) or/and TIR domain-containing adaptor-inducing interferon-β (TRIF). And then the MyD88-dependent or TRIF-dependent signaling cascade triggers the innate immune responses. TLRs-mediated signaling needs to be effectively controlled to avoid inappropriate immune response and harmful damages to the host. Speckle-type POZ (pox virus and zinc finger protein) protein (SPOP) is an E3 ubiquitin ligase adaptor protein which is involved in cancer development and progression. Still, its role in innate immunity remains unclear. In our pilot study, we found SPOP could interact with MyD88 and inhibit TLRs-mediated inflammatory cytokines expression. In this study, we propose to identify the molecular target of SPOP and to investigate the mechanism of negative regulation of TLRs signaling by SPOP. This study contributes to the elucidation of complicated molecular mechanisms of TLRs signaling, and provides new evidences that the cancer-related protein participated in the regulation of the innate immune responses.

TLRs是一类重要的模式识别受体，在机体抵御病原微生物感染过程中发挥着十分关键的作用。TLRs识别病原体的保守组分后，能够招募下游接头蛋白MyD88或/和TRIF，随后诱发胞内一系列信号级联反应，启动天然免疫。TLRs介导的信号传递过程必须受到严格而精细的调控以防止过强或不足的免疫反应对机体造成伤害。SPOP是E3泛素连接酶Cullin3的接头蛋白，在肿瘤发生、发展中发挥重要作用，但其是否参与天然免疫信号转导过程尚无报道。申请人在前期的工作中发现，SPOP与MyD88有相互作用且能够抑制MyD88依赖的TLRs信号通路介导的炎症因子表达。本项目计划进一步锁定SPOP的分子靶标，解析其调控TLRs信号通路的具体分子机制。该项目的成功完成，不仅对阐述TLRs信号通路转导过程及其精细调控机制作出贡献，而且对肿瘤相关蛋白在天然免疫应答过程中的重要调控作用提供新的范例。

本项目围绕TLRs介导的天然免疫信号转导通路进行了基础研究工作。我们发现SPOP能够负调节TLRs介导的炎症因子表达，并阐明了其发挥作用的分子机制。本研究的结果将有利于为TLRs通路异常引发的疾病提供分子靶标及新的治疗策略。项目执行期间已经发表标注自然基金资助的SCI论文1篇（IF＞5）,另有一篇正在修回中。