SIRT5调节巨噬细胞代谢在结肠炎-结肠癌恶性转化中的作用和分子机理

The Warburg effect of cancer cell is the ability to acquire glucose from a frequently nutrient-poor environment and utilize these glucose to both maintain ATP and build new biomass. Metabolic competition of tumor cells and TILs(tumor infiltrating lymphocytes) within the tumor niche directly dampen TILs’s effector function and allowing tumor progression. Is it possible to correct this resource imbalance through reprogramming immune cells metabolism? The deacylase sirtuin 5 (SIRT5) catalyzes the removal of lysine malonylation, succinylation, and glutarylation from a wide range of proteins in different metabolic pathways. We found the emerging role of SIRT5 in tumor metabolism regulation, macrophage metabolism, dextran sodium sulfate-induced colitis in mice and downregulation in colitis-associated cancer (CAC). However, the regulation of immunometabolism and inflammation by SIRT5 independent of their role in modulating tumor metabolism remains largely unknown. We think the SIRT5 has an important role in CAC by regulating resource imbalance in the tumor microenvironment. Here, we are going to discover the function and mechanism of SIRT5 in progression of CAC. The first part is to induce CAC model in wild type and Sirt5 knockout mice ( myeloid cell specific knockout) by dextran sulfate sodium (DSS) plus azoxymethane (AOM). The second part is to characterize the metabolism of tumor associated macrophages (TAMs) in different stage of CAC. The last part is to determine functional consequence of metabolic rearrangement by regulating SIRT5 function and activity.. New efforts to target cancer should incorporate the idea that metabolic competition occurs in tumors and this can influence tumor progression. Future therapies may consider combining treatments that dampen tumor metabolism with those that enhance TILs nutrient acquisition in order to promote optimal antitumor immunity.

肿瘤细胞利用糖酵解产生能量和代谢中间物赋予其自身内在生长优势，新近研究表明这种Warburg效应还为肿瘤细胞提供一种外部优势：肿瘤造成的代谢限制，重组了免疫细胞代谢状态，抑制了免疫细胞活性和抗肿瘤能力。那么是否可以通过重编程免疫细胞代谢，彻底解放被肿瘤抑制的免疫系统，构建肿瘤治疗新方式？SIRT5是与代谢密切相关的赖氨酸去酰基化酶。我们研究发现：SIRT5可以抑制肿瘤细胞代谢；抑制巨噬细胞糖酵解和小鼠结肠炎。鉴于巨噬细胞在结肠炎癌转化中的重要作用，我们提出SIRT5是否通过协调肿瘤代谢和免疫代谢平衡，调控结肠癌发生发展？本项目拟构建Sirt5条件敲除小鼠结肠炎癌模型、解析结肠炎癌转化三个关键阶段的巨噬细胞代谢格局、调控SIRT5活性“重编程”巨噬细胞代谢以抑制结肠癌等，来研究SIRT5调控免疫代谢在结肠癌中的功能和机制。本研究将深入阐明免疫代谢在肿瘤中的作用机理，从而为肿瘤治疗提供新方法。

Sirtuins是一类去酰基化酶蛋白家族，含有SIRT1-7共7个成员，在肿瘤等疾病发生发展中有重要作用 。我们针对Sirtuins 家族中唯一已知的，同时具有去琥珀酰化、去丙二酰化和去戊二酰化功能的SIRT5进行系统研究，发现其主要通过调控糖酵解和三羧酸循环中多个代谢酶的蛋白质翻译后修饰，调控了肿瘤代谢和免疫代谢，我们不仅系统地阐述了SIRT5 的功能和分子机制，还创新性地发现SIRT5可以调控炎症和炎癌转化为控制炎症性疾病提供了新靶点。我们揭示了SIRT5对PKM2的翻译后修饰水平及其酶活性的调节机制；SIRT5的缺失导致细胞内PKM2的琥珀酰化修饰水平明显上调，显著抑制其丙酮酸激酶的活性，并促进PKM2四聚体到二聚体的转变，使其蛋白激酶活性明显增强。我们阐述了LPS活化后的巨噬细胞中SIRT5对PKM2的琥珀酰化修饰水平及其酶活性的调节作用，以及该过程对炎症因子IL-1β的调控作用，发现SIRT5通过调控巨噬细胞代谢影响小鼠急性结肠炎的发生和发展。研究结果发表在2017年的Cell reports杂志。生物谷、BioArt和精准医学与蛋白质学平台等对本工作进行了广泛报道。2018年Trends in Immunology 杂志发表Immunometabolism专刊，引用了我们的工作，并提到SIRT5可以作为一个关键因子，协同调控乙酰化与琥珀酰化修饰的交互应答。接着，我们又发现SIRT5通过调控巨噬细胞与胰岛细胞的相互作用，通过调节葡萄糖稳态，调节小鼠的抗感染能力。研究结果发表在2020年的Protein Cell杂志。在本项目资助下，共发表4篇研究论文。