TRIM7调控STING信号转导的新机制研究

The innate immune signaling pathways are subjected to myriad post-translational modifications in response to the intrinsic and environmental cues. Ubiquitination has been demonstrated to serve as an effective means to catalyze the rapid, dynamic and versatile regulatory processes that are activated when hosts face microbes. Given the critical functions of STING-dependent cytosolic DNA sensing pathway in anti-viral innate immune responses, they are subjected to manifold spatial and temporal modulations shaping the strength and duration of the signaling pathways. However, it remains to be elucidated whether ubiquitination could modulate the STING-dependent signaling pathway. In an expression screen for proteins that can activate the IFN-β promoter, we identified E3 ubiquitin ligase TRIM7 as a critical regulator in anti-viral signaling pathways. According to the preliminary results, we found that TRIM7 is indispensable for DNA-triggered antiviral signaling but has no effect on exogenous RNA-induced immune response. This study will further investigate the regulatory mechanisms of STING-mediated signaling by TRIM7, as well as the essential physiological and pathological functions of TRIM7 in anti-microbial immune responses, which will bring a fresh perspective on the prevention and treatment of diseases caused by pathogenic microorganism infection.

泛素化修饰可以丰富固有免疫信号通路的动态可塑性，便于宿主细胞应答各种感染入侵，以及内外环境变化。STING（stimulator of interferon genes）介导的外源DNA识别信号通路在宿主应答病原微生物侵染过程发挥了关键作用，该信号通路的强度以及持续时间受到精确的调控。然而泛素化修饰如何调控STING介导的信号通路仍然有待深入研究。本实验室通过系统的功能性筛选，发现E3泛素连接酶TRIM7具有潜在的抗病毒功能。在本项目中，我们初步发现TRIM7可以特异调控STING介导的外源DNA识别信号通路，而不能调控外源RNA识别信号通路。本项目将重点研究TRIM7调控STING介导的信号转导通路的具体分子机制，以及TRIM7在抗病原微生物感染中的关键生理与病理功能，为预防和治疗病毒或细菌感染引起的相关疾病提供新的思路。

天然免疫是宿主防御病原微生物入侵的第一道防线，宿主细胞的模式识别受体识别病原微生物的保守组分如核酸分子，感知病原微生物的入侵，通过相关信号转导级联反应，最终诱导I型干扰素以及炎症因子的表达。RNA识别以及RNA识别后的信号转导机制在过去的十多年已经被详细解析，然而微生物DNA、细胞内自身DNA识别以及DNA识别后的信号转导机制的研究最近几年才开始起步。.宿主检测到外源入侵的DNA后可以迅速产生免疫反应并最终通过获得性免疫反应清除病原微生物，然而从细胞核以及线粒体泄露到胞质中的自身DNA被宿主识别将会诱发自身免疫病，比如系统性红斑狼疮以及Aicardi Goutières综合征，因此非常有必要深入的研究DNA识别以及相关的信号转导调控机制，这无疑对病原菌感染相关疾病以及自身免疫病的治疗具有积极的意义。.在胞质DNA刺激情况下，环化GMP-AMP合成酶 cGAS可以催化GTP 和ATP反应生成第二信使分子2′3′-cGAMP, 随后该信使分子结合STING 激活进而下游信号，然而并不清楚cGAS酶活是如何被精确调控的。我们发现定位在内质网上的E3 泛素连接酶RNF185在HSV-1感染情况下与cGAS发生相互作用并催化了cGAS的K27链型的多聚泛素化修饰，从而增强了cGAS的酶活活性，另外，系统性红斑狼疮病人血液中表现出了上调的RNF185 mRNA的表达。我们首次报道了作用于cGAS的第一个泛素连接酶，并且阐述了cGAS的酶活调控机制。