SENP1-Sirt3轴调控免疫细胞代谢重编程及在抗肿瘤免疫中的作用与机制

We previously found that deacetylase Sirt3 catalytic activity was suppressed by SUMOylation in mitochondria. During metabolic stress, SUMO-specific protease SENP1 was accumulated in mitochondria and quickly de-SUMOylated and activated Sirt3, which modulated metabolic program in mitochondria. We also demonstrated that the mice with SUMOylation deficiency altered the function of immune cells. Meanwhile, xenograft tumor in the mice with SUMOylation deficiency grew faster than that in control mice. Therefore, we hypothesize that tumor microenvironment triggers SENP1-Sirt3 axis in immune cells, which undergo metabolic reprogramming and modulates anti-tumor immunity. We will perform experiments to determine: 1) the role of SENP1-Sirt3 axis in regulation of immune activities in T cells and macrophages; 2) the role of SENP1-Sirt3 axis in modulating metabolic program in T cells and macrophages; 3) How tumor microenvironment triggers SENP1-Sirt3 axis in immune cells; 4) the role of SENP1-Sirt3 axis in modulating anti-tumor immunity of immune cells during tumorigenesis. These studies will provide us insight into metabolic reprogramming in immune cells in anti-tumor immunity.

我们发现代谢应激促进SENP1进入线粒体中，调控Sirt3的SUMO修饰和活性及相关线粒体的代谢。进一步发现Sirt3 SUMO位点突变的小鼠免疫细胞活性改变，并与肿瘤生长相关。基于此，我们假设Sirt3的SUMO修饰能够调控免疫细胞线粒体代谢和功能，在肿瘤微环境的作用下，SENP1调控Sirt3的SUMO修饰，进而影响抗肿瘤免疫和肿瘤生长。本课题将研究以下问题：1）SENP1-Sirt3轴能够调控巨噬细胞和T细胞哪些功能？ 2）SENP1-Sirt3轴能够调控巨噬细胞和T细胞中哪些代谢途径？3）肿瘤微环境有哪些代谢应激因素能够及如何调控SENP1-Sirt3轴的活性？4）SENP1-Sirt3轴对抗肿瘤免疫的调控作用是否与肿瘤病理过程有关？这些研究将明确SENP1-Sirt3轴在调控免疫细胞代谢及抗肿瘤免疫中的作用与机制。

本课题主要围绕SENP1-Sirt3轴调控免疫细胞代谢重编程及在抗肿瘤免疫中的作用与机制进行了研究。按照课题计划安排，我们的研究取得了如下成果： 1. 鉴定了SENP1-Sirt3轴在调控线粒体的乙酰化修饰和代谢中的作用（Molecular Cell, 2019），明确了SENP1-Sirt3轴是线粒体代谢应激反应调控的关键信号通路；2. 发现了葡萄糖限制激活AMPK和SENP1-Sirt3轴调控CD8+记忆性T细胞形成 (Nature Communications, 2021)。这一结果回答了SENP1-Sirt3轴在由效应性T细胞分化形成记忆性T细胞的过程中到代谢重编程的调控作用以及在抗肿瘤免疫中的意义；3. 发现了SENP1-Sirt3轴调控巨噬细胞谷氨酰胺代谢促进M2型极化的作用与机制 (Cell Reports, 2022)。这一结果表明了SENP1-Sirt3轴调控线粒体代谢活性联合表观遗传机制在巨噬细胞M2极化中的作用与意义。这些结果揭示了SENP1-Sirt3轴是免疫细胞活化过程中线粒体代谢重编程的一个关键信号通路，对免疫细胞活化和免疫反应有重要调控作用。