STRIPAK复合物的结构组装与抗感染免疫功能调控

Striatin-interacting phosphatase and kinase (STRIPAK) complex has been recently identified as a conserved multi-functional superamolecular complex. STRIPAK is mainly composed of striatins, phophatases like protein phosphatase 2A (PP2A), kinases like germinal center kinases (GCKs), and other accessory proteins. STRIPAK complex localizes to the nuclear envelope, endoplasmic reticulum structures, and centrosomes. The representative kinase components of STRIPAK are GCKIIs and GCKIIIs, a subgroup of germinal center kinases involved in various cellular process including organ size control, cell proliferation, migration and cell polarity. Dysregulation of STRIPAK complex has been associated with diseases including cancer. However, the specific function of the STRIPAK complex in anti-infectious immune regulation, as well as the signaling mechanisms behind, remains unknown. Previously we have studied the structure and function certain STRIPAK components (Cancer Cell, Structure 2, JBC). In this project, the applicant will take advantage of our previous knowledge of the STRIPAK complex and continue investigating its structure and assembly at complex level, aiming to define the biochemical features of the whole complex. Meanwhile, with the guidance of the 3D information, we will study the regulatory machinery of STRIPAK relevant to anti-infectious immune response. Our preliminary studies have shown that GCKs indeed play a role in anti-infectious response of the host cell. Moreover, it appears that the assembly of STRIPAK complex is essential for this type of anti-infectious immune regulation. Based on these work, we will extend our study to further dissect the functional role and structural mechanism of STRIPAK complex to resolve its regulatory nature in anti-infectious signaling.

STRIPAK复合物是由磷酸酶和激酶形成的进化保守的多组份复合物。GCKII和GCKIII家族成员是STRIPAK复合物的重要激酶组份，调控组织器官大小、细胞生长、迁移、极性等。STRIPAK复合物可定位于细胞膜、核膜、中心体等，其功能异常与癌症等重大疾病密切相关。我们前期针对STRIPAK复合物开展了一系列研究，取得了前沿性成果（Cancer Cell、Structure 2篇、JBC）。鉴于STRIPAK复合物在感染免疫中功能机制尚未明晰。申请人拟继续深入研究其动态组装与调控，着重探索其抗感染免疫的功能作用与信号机理。我们初步研究发现GCK调控抗感染免疫应答，而靶向STRIPAK复合物组装的GCK突变体则无此效应，提示该复合物组装与其抗感染免疫调控功能紧密相关。在此基础上，本项目将从复合物整体组装与调控、感染性疾病模型、免疫信号转导等方面，阐释STRIPAK复合物的感染免疫功能与机制。

STRIPAK (Striatin-interacting phosphatases and kinases) 复合物是一类在进化过程中高度保守的超分子复合物。该复合物既含有以STRN家族作为调节亚基的PP2A磷酸酶组分，又包含MST等激酶家族成员；除此之外，SLMAP、SIKE1、STRIP1/2、MOB4等也被鉴定为其核心组分。STRIPAK复合物已被报道参与调控包括Hippo信号通路在内的多种生理及病理过程。我们从STRIAPK 复合物的组装调控和功能机制两个方面展开研究，将二者结合紧密起来，在三维结构信息指导下，综合解析其功能机制，并提出潜在药物靶点和干预策略。本项目系统研究了STRIPAK复合物的拓扑结构与动态组装，发现PP2A的调节亚基STRN3作为核心支架蛋白，除了能够直接与Hippo激酶相互作用外，还可以通过两个分子“手臂”以磷酸化依赖的方式“拥抱”Hippo激酶：其中一个手臂是STRIP1，另一个手臂是SIKE1-SLMAP。在解析STRN3-SIKE1以及SIKE1-SLAMP亚复合物的高分辨率三维结构基础上，进一步发现，细胞密度降低能够引发STRIP1的解离，从而揭示了STRIPAK复合物作为Hippo通路上游对不同信号或刺激进行动态感应和集成的功能作用。而STRIPAK复合物中的激酶组分MST4在天然免疫中直接磷酸化TRAF6，影响其寡聚与泛素化活性，从而调控TLR信号通路的功能与机制。这些都为今后深入探究STRIPAK复合物与Hippo通路奠定了基础。