高尔基体上干扰素基因刺激蛋白(STING)囊泡的排出在STING下游信号通路活性调控中发挥重要作用，然而参与控制STING囊泡从高尔基体上排出的分子实体及关键机制至今仍是未知的。我们前期研究工作提示布雷菲德菌A抑制型鸟苷酸交换蛋白1（BIG1）很可能通过介导ARF3活化调控高尔基体上STING囊泡排出，从而影响STING下游信号激活程度，并在抗肺癌免疫反应及治疗中发挥重要作用（科学假说）。本项目拟对肺癌患者的临床标本进行收集与分析，并利用髓系细胞BIG1条件敲除小鼠探索BIG1缺失对肺癌免疫反应及STING激动剂抗肺癌免疫治疗效果的影响，以及利用小鼠原代树突状细胞探索BIG1或ARF3缺失对STING水平、下游信号活性、胞内分布及转运等方面的影响对上述假说进行验证。本项目的实施将为靶向调控高尔基体上STING囊泡排出的关键因子BIG1来增强STING信号从而增强抗肺癌免疫反应提供实验依据。

The exit of stimulator of interferon genes (STING) vesicles from Golgi plays an essential role in the regulation of STING-dependent downstream signaling activity, however, the molecular entities and key mechanisms involved in controlling STING vesicles exiting from Golgi still remain poorly understood. Our latest work suggests that Brefeldin A-inhibited guanine nucleotide-exchange protein 1 (BIG1) is likely to regulate the exit of STING vesicles from Golgi by mediating ARF3 activity, thereby affecting the degree of activation of STING-dependent downstream signaling, and playing an important role in anti-lung cancer immune response (Scientific Hypothesis). In this project, we will verify the above scientific hypothesis by collecting and analyzing human lung cancer specimens, and taking advantage of myeloid cell lineage BIG1 conditional knockout mice to study the effects of BIG1 deficiency on anti-lung cancer immune response and anti-lung cancer immunotherapy of STING agonist, and taking advantage of mouse primary bone marrow-derived dendritic cells to study the effects of BIG1 or ARF3 deficiency on STING levels, STING-dependent downstream signaling , STING intracellular distribution and trafficking. The implementation of this project will provide an experimental basis for targeting and regulating BIG1, a key factor in mediating the exit of STING vesicles from Golgi, to enhance STING-dependent downstream signaling and anti-lung cancer immune response.