Merlin及天然突变体调控细胞质核酸免疫识别通路的功能与机制研究

Loss-of-function mutation or deletion of tumor suppressor NF2/Merlin is the leading causation for development of type 2 neurofibromatosis, and also responsible for occurrence of various malignants including mesothelioma, breast and prostate cancer. Current studies for dissection of Merlin-induced tumorigenesis are mainly focused on its regulatory role in cell proliferative signaling pathways. Merlin's function in anti-tumor immunity has remained unclear and waits to be defined. Cytosolic nucleic acid sensing is a new developed research area and numerous reports pointed to its critical role in modulation of anti-tumor immunity. On the basis of preliminary evidence that Merlin may involve in regulation of innate immune sensing of nucleic acids, this proposed study will focus on the function and mechanism investigations of Merlin and its naturally occurred mutants in control of cytosolic nucleic acid sensing, and through this regulation, the potential control of anti-tumor immunity. The study utilizes the systems of gene expression, signal transduction, as well as cell and animal models, and pays attention to both the critical scientific issue as well as the demands of national interest. Successfully implemented project might provide a new strategy on prevention and cure of multiple tumors related to Merlin mutation and deletion.

抑癌基因NF2编码蛋白Merlin的突变或缺失是引发二型神经纤维瘤的主要诱因，其突变也常出现于间皮瘤、乳腺癌、前列腺癌等多种恶性肿瘤。但目前关于Merlin蛋白的抑癌机制研究主要集中于细胞增殖相关信号通路，其在抗肿瘤免疫中的功能尚未探讨。细胞质核酸免疫识别系统的抗肿瘤免疫功能与机制是当前生物医学研究的国际前沿之一。本研究项目将围绕“Merlin蛋白及其天然突变体调控细胞质核酸免疫识别通路的功能和分子机制”这一关键科学问题，从基因表达、信号通路控制、细胞和动物肿瘤模型等多方位着手，研究Merlin蛋白及突变体调控细胞质核酸免疫识别系统，进而影响肿瘤发生的关键分子机制。本研究内容充分兼顾了重要科学问题与国家实际需求，项目的顺利实施将为Merlin蛋白相关肿瘤防治提供全新策略，并且具有潜在的应用前景。

肿瘤抑制因子NF2（Merlin）N端FERM结构域发生突变后，导致NF2蛋白的功能失活，进而促进多种器官的肿瘤发生。但是关于NF2及其点突变在抗肿瘤免疫中的调控作用目前鲜有研究。本研究发现NF2通过调节YAP/TAZ的活性促进先天免疫响应，而来自II型神经纤维瘤病人中的NF2突变（FERM结构域错义突变，NF2m）对cGAS-STING 信号通路有强烈的抑制作用。机制上，细胞质核酸识别信号激活后，活化的IRF3 可以诱导NF2m形成液滴状聚集体。NF2m聚集体与RLR-MAVS/cGAS-STING信号的下游效应蛋白TBK1和IRF3 发生强相互作用，同时招募多种蛋白酶，包括磷酸酶PP2A去磷酸化并失活TBK1。功能上，在小鼠抗肿瘤免疫模型中，NF2m强烈抑制STING介导的细胞自主和非自主的抗肿瘤免疫。综上，本研究阐述了肿瘤抑制因子NF2发生突变后可以被cGAS-STING信号诱导形成相分离，负调控先天免疫响应的新机制，并且获得抑制肿瘤免疫的新功能，同时为治疗NF2相关肿瘤提供了新思路。