FlaAN/C蛋白介导的hNAIP-NLRC4炎性小体自噬对辐射性细胞焦亡的调控机制研究

细胞焦亡是辐射炎性损伤的重要原因，项目组自主知识产权鞭毛重组蛋白FlaA N/C显著抑制辐射性细胞焦亡，其机制尚未阐明。结合前期研究，项目组推测，静息状态下，NLRC4与Beclin-1以复合物形式存在，FlaA N/C蛋白通过其胞内受体hNAIP竞争性募集NLRC4形成hNAIP-NLRC4-ASC炎性小体复合物，而游离的Beclin-1进而介导hNAIP-NLRC4-ASC炎性小体复合物自噬，消耗胞内ASC等分子，从而抑制后续辐射性细胞焦亡的发生。本项目拟结合细胞和动物模型，探讨FlaA N/C蛋白介导hNAIP-NLRC4炎性小体自噬及其对辐射性细胞焦亡发生的调控机制；并在结构生物学水平，系统阐述FlaA N/C蛋白活化的hNAIP竞争性Beclin-1结合NLRC4的分子位点机制。通过本项目的实施可系统阐明FlaA N/C蛋白的辐射防护机制，为相应辐射性防护制剂研究提供新的策略。

Pyroptosis is an important cellular process in radiation-induced inflammatory injury. Our independent intellectual property rights biological agents FlaA N/C, a recombinant protein based on flagellin of Legionella pneumophila, significantly inhibits radiation-induced pyroptosis. While, its mechanism has not been fullly clarified. Our previous studies speculated that NLRC4 and Beclin-1 exist as an complexes in resting cells. FlaA N/C proteins competitive recruit NLRC4 to form hNAIP-NLRC4-ASC inflammasome through its intracellular receptor hNAIP. Beclin-1 then mediates autophagy of hNAIP-NLRC4-ASC inflammasome and consumes intracellular ASC molecules, thereby inhibiting subsequent radiation-induced pyroptosis. This project aims to explore the mechanism of FlaA N/C mediated autophagy of hNAIP-NLRC4 inflammasome and its regulation mechanism in radiation-induced pyroptosis in vivo and vitro, and the molecular sites of hNAIP activated by FlaA N/C protein competitive Beclin-1 binding NLRC4 by structural biology. Implementation of this project can systematically clarify the radiation protection mechanism of FlaA N/C protein, and provide a new strategy for researching of radiation protection agents.