SENP1-TFEB轴调控巨噬细胞自噬溶酶体生成的机制及与动脉粥样硬化的关系

Autolysosome plays an important role in promoting the outflow of cholesterol in macrophages and inhibiting the formation of atherosclerotic foam cells. TFEB is a key transcription factor that regulates autolysosomes. We found that knockout of SUMO protease 1 (SENP1) inhibited the formation of macrophage foam cells and atherosclerosis; SENP1 can regulate the SUMO modification of TFEB; SUMO modification regulates the transcriptional activity of TFEB and affects the production of autolysosomes. Therefore, we suggest that the SENP1-TFEB axis regulates the generation of autolysosomes, which affects the formation of macrophages and the development of atherosclerosis. In this study, we will focus on the following questions: 1. Does SENP1-TFEB axis regulate the formation of autolysosomes? 2. How SENP1 regulates the TFEB transcriptional activity? 3. How extracellular signal regulates SENP1 activity? 4. What is the role of SENP1-TFEB axis in the regulation of atherosclerosis development? This project will make us further understanding the role and mechanisms of SENP1-TFEB axis on autophagy and atherosclerosis, and will contribute to the novel opportunities for targeting atherosclerosis.

自噬溶酶体是促进巨噬细胞内胆固醇流出及抑制动脉粥样硬化泡沫细胞形成的重要结构，TFEB是调控自噬溶酶体的关键转录因子。我们发现敲除去SUMO化蛋白酶1（SENP1）能抑制巨噬泡沫细胞形成和动脉粥样硬化；SENP1能够调控TFEB的SUMO化修饰；SUMO化调控TFEB的转录活性并影响自噬溶酶体生成。因此，我们提出SENP1-TFEB轴调控自噬溶酶体的生成，影响巨噬泡沫细胞形成和动脉粥样硬化的发生发展。本课题将研究如下科学问题：1. SENP1-TFEB轴在自噬溶酶体生成中的调控作用；2. SENP1-TFEB调控自噬溶酶体生成的分子机制；3.胞外信号调控SENP1活性的机制；4. SENP1-TFEB轴调控自噬溶酶体生成在动脉粥样硬化发生发展中的作用。回答这些问题将使我们深入认识SENP1-TFEB轴在自噬和动脉粥样硬化中的意义。

自噬溶酶体是促进巨噬细胞内胆固醇流出及抑制动脉粥样硬化泡沫细胞形成的重要结构，TFEB是调控自噬溶酶体的关键转录因子。我们发现敲除去SUMO化蛋白酶1（SENP1）能抑制巨噬泡沫细胞形成和动脉粥样硬化；相比野生型巨噬细胞，senp1-/-巨噬细胞具有更强的自噬和溶酶体功能，以及溶酶体和自噬相关基因表达；SENP1能够调控TFEB的SUMO化修饰；SUMO化调控TFEB的转录活性并影响自噬溶酶体生成。这些研究结果使我们深入认识SENP1-TFEB轴在巨噬细胞脂噬和动脉粥样硬化中的意义。同时，我们利用条件敲除小鼠模型发现了巨噬细胞调控血脂的新机制，进一步的深入研究将会获得巨噬细胞功能的新发现。