内质网中蛋白质氧化折叠及其调控的新机制

二硫键对于分泌蛋白和膜蛋白的结构与功能十分重要，在内质网中由蛋白质二硫键异构酶（PDI）家族成员催化形成。PDI需被巯基氧化酶Ero1重新氧化才能使二硫键不断传递到底物蛋白。Ero1利用O2作为电子受体，每产生一分子二硫键的同时产生一分子H2O2。蛋白质合成旺盛的分泌细胞中大量H2O2的产生具有潜在的毒害作用。本项目拟在不同层面研究细胞如何应对氧化折叠过程中产生的H2O2。（1）研究PDI及其若干家族成员激活和失活Ero1的反馈调控机制；（2）研究内质网中新发现的过氧化物酶GPx7在Ero1/PDI系统中的作用，并阐明其催化机制；（3）探索新的由GPx7介导的细胞氧化应激保护通路。这些研究将为阐明高等真核生物内质网中的氧化折叠通路及其调控的机制贡献新的重要信息，并有助于揭示和内质网应激密切相关的疾病（如2型糖尿病）的分子机理。

Disulfide bond is vital for the structure and function of most secretory and membrane proteins. In the endoplasmic reticulum (ER), disulphide bond formation is enzymatically catalysed by members of the protein disulphide isomerase (PDI) family. Ero1 sulfhydryl oxidases re-oxidise PDI to allow a continuous transfer of disulphides to substrate proteins. Ero1 uses O2 as an electron acceptor, producing equimolar H2O2 for each disulphide formed. The large amount of H2O2 produced in professional secretory cells is potentially harmful. This project aims to study how cells deal with excess H2O2 produced during oxidative folding in different aspects. (1) We will study the feedback regulation mechanisms, by which PDI and its family members activate and inactivate Ero1. (2) We will investigate the roles and the catalytic mechanism of newly identified ER-located glutathione peroxidase 7 (GPx7), in the Ero1/PDI system. (3) We will explore potential oxidative stress-induced cellular protective pathway mediated by GPx7. Our studies will contribute important information to the illustration of the oxidative folding pathway and its regulation mechanism in the ER of higher eukaryotes, and will provide new insights into the molecular mechanisms of ER stress related diseases (e.g. type 2 diabetes).