抗DNA病毒天然免疫关键蛋白STING促进脂肪合成代谢的分子机制研究

脂肪代谢紊乱与肥胖、脂肪肝、高血脂等多种代谢性疾病的发病密切相关。Insig/SCAP/SREBP和cGAS/STING信号通路都发源于内质网，分别控制脂肪合成代谢和抗DNA病毒的天然免疫应激，然而两者之间是否存在信号交叉仍然未知。申请人前期研究结果显示肝脏特异性敲除小鼠Sting基因能防止高脂高糖食物诱导的肥胖、脂肪肝、高血脂等疾病的发生，机制研究结果揭示Sting蛋白在小鼠饥饿状态下通过自噬降解，进食后Sting蛋白水平升高并与Scap/Srebp复合体竞争结合锚定蛋白Insig，导致Srebp进入细胞核激活脂肪合成相关基因的表达。申请人将通过体内小鼠模型、体外生化和培养细胞实验进一步研究揭示Sting调控脂肪合成代谢的生物学功能。本研究的完成有望拓展STING抗DNA病毒天然免疫以外的生物学功能，为制定脂肪代谢紊乱相关疾病的防治策略提供理论依据。

Abnormal lipogenesis is related to many metabolic diseases including liver steatosis, obesity, and hyperlipidaemia. Insig/SCAP/SREBP and cGAS/STING signaling axes derived from endoplasmic reticulum (ER) control lipogenesis and innate immunity against infections of DNA viruses. However, the crosstalk between these two pathways remains largely unknown. Preliminary data demonstrate here that mice with liver-specific Sting knockout are resistant to liver steatosis, obesity, and hyperlipidaemia induced by high-fat and high-sucrose (HFHS) diet. Mechanistically, Sting is subjected to autophagy-mediated degradation under fasting condition and refeeding stabilizes Sting by inhibiting autophagy. Upregulated Sting interrupts the Insig/Scap/Srebp complex by competitively binding to Insig, which is an anchor protein locating on ER, leading to Srebp activation and expression of lipogenesis genes after feeding of mice. The biological role of Sting on modulation of lipogenesis would be further investigated by using analyses of mouse model in vivo, biochemical assays and cell culture experiments in vitro. Completion of this study would uncover the biological roles of STING besides anti-DNA virus innate immunity and provide the therapeutic opportunities for preventing and treating metabolic diseases caused by lipogenic abnormality.