USP25通过Lyn去泛素化调控BCR信号和体液免疫应答的机制研究

USP25 is essential for fighting against viral infection during innate immunity. However, there is no related report about the role of USP25 in humoral immunity. Our previous study showed that USP25 interacts with Lyn during BCR signaling activation, moreover, loss of USP25 leads to the accelerated degradation of Lyn and decreased activity of the downstream molecules of Lyn, thus leads to the abnormal of B cell differentiation and immune response. During the activation of BCR signaling, the ubiquitination level of Lyn is negatively correlated with the strength of BCR signaling, but it is still unclear that whether the interaction of USP25 with Lyn can inhibit the ubiquitination of Lyn to regulate BCR signaling. In order to investigate these questions, this study is going to use USP25-KO mice and USP25-KO A20 cells to study the molecular mechanism of USP25 to regulate BCR signaling through deubiquitinating Lyn. This study provides the theoretical foundation to further clarify the mechanism of the ubiquitination system to regulate BCR signaling and the sequential regulation of B cell differentiation and humoral immune response.

USP25对于抵抗病毒感染的作用是必不可少的。然而，关于USP25在体液免疫中的作用未见相关报道。在前期研究中我们发现BCR信号激活时，USP25与Lyn发生相互作用。USP25缺失导致Lyn降解加快和Lyn下游分子活性下降，进而导致B细胞分化和免疫应答异常。在BCR信号激活中，Lyn泛素化水平与BCR信号强度呈负相关。USP25和Lyn相互作用是否能抑制Lyn泛素化调控BCR信号并不清楚。为了探索这些问题，本研究利用USP25-KO小鼠和USP25-KO A20细胞系探索USP25通过Lyn去泛素化调控BCR信号的分子机制。本研究为进一步阐明泛素系统调控BCR信号的机制从而调控B细胞分化和体液免疫应答奠定理论基础。

研究背景：.前期研究结果表明BCR信号激活时，USP25与Lyn发生相互作用。USP25缺失导致Lyn降解加快和Lyn下游分子活性下降，进而导致B细胞分化和免疫应答异常。.研究内容：.本研究以Usp25 KO小鼠为研究对象，探究USP25 缺失对B细胞发育分化、激活后BCR信号转导和体液免疫应答的影响。.研究结果：.USP25 的缺失阻碍 MZ和GC B细胞的分化。USP25正向调节近端CD19和BTK的激活，负向调节SHIP1的激活。并且Usp25 KO B细胞激活后，WASP的激活和F-actin的积累增强。在机制上，我们发现USP25缺失可促进Lyn的泛素化，从而导致BCR信号的下调。USP25的缺失导致免疫后或日本血吸虫感染后体液免疫反应受损。.研究意义：.通过USP25基因敲除小鼠模型探究发现USP25可通过Lyn去泛素化调控BCR信号和体液免疫应答，本研究为进一步阐明泛素系统调控BCR信号的机制从而调控B细胞分化和体液免疫应答提供了实验依据。