蛋白的SUMO化修饰在胸腺T发育和分化中的作用

Protein SUMOylation is a post-translation modification in eukaryotic cells, which plays important roles in various biological processes such as gene transcription, chromatin remodeling, DNA replication and repair as well as numerous human disease. It was reported that SUMOylation negatively regulates immune response by restraining inflammation cytokines production in myeloid cells. However, physiological consequence of SUMOylation deficiency in T cells remains to be determined. Ubc9 is the critical enzyme for SUMOylation and Ubc9 deletion will abolish the whole SUMOylation pathway. In this study, taking advantage of Ubc9fl/fl CD4cre mouse model, we selectively inactivate SUMOylation in the early developmental stage of thymocytes to decipher the role of SUMOylation in T cell positive selection and post-selectional maturation. Furthermore, we will detect the function of SUMOylation in TCR and cytokine signals, the gene regulation network in T cell development and differentiation. Finally we will define the critical substrates in n T cell by Mass-spec, and decipher how SUMOylation regulates the function and activity of this substrate.

SUMO化修饰是一类存在于真核细胞中的蛋白翻译后修饰，在基因转录调控、染色体重塑、DNA复制与修复等方面发挥重要作用，也与人类众多疾病的发生密切相关。目前的研究表明在先天性免疫系统中SUMO化修饰能够抑制炎症因子的产生从而负调控免疫反应，但是其在适应性免疫系统中的作用仍有待探究。UBC9是催化SUMO化修饰的关键酶，敲除Ubc9会导致SUMO化修饰不能完成。本研究将利用Ubc9fl/fl CD4cre小鼠模型在胸腺T细胞发育早期敲除Ubc9，研究SUMO化修饰在T细胞阳性选择和选择后成熟过程的作用。同时，本研究将利用生化手段探究SUMO化修饰对TCR信号和细胞因子信号通路的调控作用；通过转录组和ChIP-Seq分析揭示SUMO化修饰在T细胞发育和分化过程的基因调控网络；通过质谱分析揭示T细胞中发生SUMO化修饰的关键蛋白，并进一步阐明SUMO化修饰对底物蛋白功能和活性的调控。

SUMO化修饰是一类存在于真核细胞中的蛋白翻译后修饰，在基因转录调控、染色体重塑、DNA复制与修复等方面发挥重要作用，也与人类众多疾病的发生密切相关。目前的研究表明在先天性免疫系统中SUMO化修饰能够抑制炎症因子的产生从而负调控免疫反应，但是其在适应性免疫系统中的作用仍有待探究。UBC9是催化SUMO化修饰的关键酶，敲除Ubc9会导致SUMO化修饰不能完成。本研究将利用Ubc9fl/fl CD4cre小鼠模型在胸腺T细胞发育早期敲除Ubc9，研究SUMO化修饰在T细胞阳性选择和选择后成熟过程的作用。我们发现Ubc9的缺失显著影响了CD4和CD8T细胞在胸腺和外周的发育。Ubc9缺失的T细胞存在阳性选择后的成熟缺陷，表现为凋亡的增多和增殖障碍，其中IL-7信号通路的减弱与Ubc9缺失的CD8SP细胞的存活降低显著相关。同时，我们发现TCR信号介导的NFAT转录因子在细胞核的锚定在胸腺细胞的发育过程中受到SUMO化修饰的调控。总之，我们的研究揭示了一种新型的蛋白翻译后修饰机制对T细胞早期发育的调控作用。