WDFY1在TLRs信号转导通路中的作用及其分子机制

TLRs信号转导通路在抵御病原体入侵的天然免疫效应中发挥重要作用。位于细胞膜或内体上的TLRs识别病原体保守结构后，通过依赖MyD88或者TRIF的信号转导通路活化NFkappaB，AP-1和IRF3在内的一系列转录因子，启动炎症效应和I型干扰素效应。TLRs信号转导通路的精细调控机制的研究一直是天然免疫领域的研究热点之一。我们利用荧光素酶报告基因系统筛选出了一个能协同polyI:C诱导I型干扰素表达的分子WDFY1。前期实验表明：WDFY1剂量依赖性地协同polyI:C或LPS诱导IFN-beta启动子和增强子的活化以及抗病毒蛋白的转录，提示WDFY1参与TLR3和TLR4信号转导通路的调控。本项目将进一步确定WDFY1的功能，并深入探讨其作用机制，以充实TLRs信号转导的调控机制，为寻求有效的药物干预靶点提供线索。

TLRs signaling plays critical roles in innate immunity against pathogens. TLRs,located on cell membrane or endosomes, initiate MyD88- or TRIF- dependent signal transductions after recoginizing pathogenic conserved structures. TLRs signaling activates several transcriptional factors, including NFkappaB,AP-1 and IRFs,and finally leads to inflammation or type I interferon effects to fight against pathogens. Researches on subtle regulation of TLRs signalings are hotspots of innate immunity all the time. In order to identify new molecules in regulating TLR signalings, we have performed luciferase reporter assays, and identified a new molecule, called WDFY1, which can enhance polyI:C-triggered activation of interferon beta promoter.We also found WDFY1 enhanced LPS-triggered activation of interferon beta promoter and enhancer. These results strongly suggest that WDFY1 participates in positive regulation of TLR3- and TLR4- signalings. In this project, we will further confirm the roles of WDFY1 in TLR signalings and figure out the mechanism in details. The research will replenish the theory of TLR signaling, and provide new clues for developing effective drugs.