膜蛋白TMED10调节非经典分泌分子机制的研究

非经典分泌是没有信号肽的胞浆蛋白通过不依赖内质网-高尔基体的分泌途径，与多种生理和病理过程密切相关，对其分子机制的研究是当今细胞生物学热点和难点。促炎症因子白介素（IL）-1beta是已知非经典分泌蛋白之一，其分泌途径与细胞自噬相关。我们已有研究揭示IL-1beta在分子伴侣HSP90的协助下通过去折叠直接跨膜转运进入分泌囊泡载体，提示可能有类似Translocon的膜蛋白介导此过程。通过质谱鉴定，我们发现膜蛋白TMED10参与IL-1beta的分泌。本项目将聚焦TMED10介导IL-1beta跨膜进入囊泡载体以及膜泡运输的过程，通过生化分离、细胞成像和体外重建等研究方法，解析膜蛋白TMED10介导蛋白非经典分泌过程中的功能和分子机制。

Unconventional secretion refers to the release of cytosolic proteins without a signal peptide. The process is not dependent on ER-Golgi secretory pathway. Unconventional secretion is involved in many physiological and pathological processes. Although under intensive investigation recently, the mechanism of unconventional secretion is unclear. Pro-inflammatory cytokine Interleukin (IL)-1beta, one of the well-recognized unconventional secretion proteins, is secreted through the autophagy pathway. Our previous study found that the secretion of IL-1beta requires its association with chaperon protein HSP90 and requires a process of protein unfolding and membrane translocation into vesicular carriers. This indicates the involvement of a translocon-like membrane protein in the secretory pathway. Using mass spectrometry, we have identified a membrane protein, called TMED10, which is required for IL-1beta secretion. In this project, we will focus on dissecting the molecular mechanism regarding the TMED10-mediated IL-1beta membrane entry and vesicle trafficking. The major approaches will include biochemistry, cell imaging and in vitro reconstitution.