STING结合蛋白SCI2调控STING信号通路的分子机制及其在抗肿瘤免疫应答中的作用研究

STING（stimulator of interferon genes，also known as MITA, ERIS）plays a critical role in the process of innate immune responses against infection, tumor immune surveillance and antitumor therapy. In our preliminary study, we have screened out a novel STING-interacting protein-SCI2 (STING C-terminus Interactor 2) by using GST pull down assay coupled with LC-MS/MS for protein identification. However, the role of this novel STING-interacting protein in STING signaling pathway is still unknown. In the current study, we will elucidate the functions of this protein in STING signaling transduction and also clarify the regulation mechanisms. In addition, as an important component of the mitochondrial permeability transition pore (MPTP), SCI2 is also involved in the process of chemotherapy-induced apoptosis. However, it is still not clear this process is related with STING-mediated antitumor therapy or not. Therefore, in this current study, we will use in vitro cell model and in vivo knock out tumor mouse model to clarify the regulatory role of SIC2 in STING-mediated antitumor immune response. The work from our study will deepen our knowledge on host defense against microbe infection and tumors, and also contribute to provide promising targets for developing anti-infective or antitumor drugs.

干扰素基因刺激蛋白STING(也称MITA，ERIS)在抗感染天然免疫应答和肿瘤免疫监视以及抗肿瘤治疗过程中起着关键作用。我们前期通过GST pull down联合蛋白质谱分析技术，筛选出了一个新的STING结合蛋白-SCI2(STING C-terminus Interactor 2)，其与STING信号通路的关系还未有研究报道。故本项目将探讨SCI2在STING信号通路中的作用及其调控STING信号通路的分子机制。此外，作为线粒体通透性转换孔(MPTP)的重要组分，SCI2参与了抗肿瘤化疗药物诱导的细胞凋亡过程，鉴于STING在抗肿瘤治疗中的作用，本课题还将通过体外细胞实验以及体内基因敲除肿瘤小鼠模型，深入分析病理条件下SCI2如何调控STING介导的抗肿瘤免疫应答。本项目研究将加深我们对机体抗感染和抗肿瘤免疫应答过程的认识，并为今后抗感染以及抗肿瘤药物的开发提供潜在的分子靶标。

干扰素基因刺激蛋白STING(也称MITA，ERIS)在抗感染天然免疫应答和肿瘤免疫监视以及抗肿瘤治疗过程中起着关键作用。本研究通过对STING结合蛋白-SCI2(STING C-terminus Interactor 2)在STING信号通路中的作用研究，发现STING结合蛋白SCI2能通过竞争性抑制cGAMP与STING结合，从而特异性地负向调节STING信号通路，但对TLR及RLR信号通路以及其介导的I型干扰素表达没有影响。体内实验进一步证实，SCI2能够抑制STING介导的、化疗药物诱导的I型干扰素表达。SCI2抑制剂联合肿瘤化疗药物，能够进一步促进肿瘤细胞死亡，增强化疗药物治疗效果。本项目研究对加深我们对机体抗感染和抗肿瘤免疫应答过程的认识，并为今后抗感染以及抗肿瘤药物的开发提供潜在的分子靶标。