分泌蛋白依赖跨膜货物受体在内质网出口位点分拣，富集并被包装到COPII转运囊泡中快速高效地转运到高尔基体，最终分泌至胞外。货物受体Surf4与牙相关分泌蛋白作用的缺失导致牙本质发育不全症，然而Surf4是否介导其他蛋白的转运和具体分子机制目前所知甚少。申请人前期实验显示Surf4的沉默表达阻滞了SPARCL1在未分化及分化型SH-SY5Y细胞中的分泌，因此推测Surf4是介导其在神经细胞中转运的关键货物受体。拟进一步构建多个Surf4蛋白保守区丙氨酸突变，并寻找互作蛋白，以及构建Surf4神经系统条件性敲除小鼠模型，揭示Surf4介导SPARCL1转运的分子机制，包括Surf4与COPII及SPARCL1结合的关键氨基酸，Surf4介导转运的协同因子，以及Surf4与SPARCL1作用的缺失对SPARCL1体内功能的影响。本项目将为临床上诊断和治疗蛋白分泌异常引发的疾病提供理论依据和策略。

Transmembrane cargo receptor mediates efficient trafficking of secreted proteins from ER to Golgi apparatus. Those secreted proteins are sorted, concentrated, and packaged into transport vesicles by the COPII coat protein complex destined to the Golgi apparatus. We previously found that the loss of the interaction between cargo receptor Surf4 and secreted protein DSPP caused a genetic disease called dentinogenesis imperfecta (DGI). However, the molecular mechanism and cargo’s broad spectrum of this cargo receptor mediated transport is unknown. Our preliminary data show that deficiency of Surf4 in either undifferentiated or differentiated SH-SY5Y cell lines caused abnormal trafficking of SPARCL1. Therefore, we propose that Surf4 mediates the trafficking of SPARCL1 in neural cells. In this project, we plan to screen important residues of Surf4 and its interacting proteins using cultured cells as the model. Meanwhile, we plan to find the effect of Surf4 on the trafficking and function of SPARCL1 using brain-specific knockout mouse model of Surf4. The goal of this project is to uncover the important roles of Surf4 and the molecular mechanisms in the early secretory pathways. Identifying the cargo and the interacting proteins and molecular mechanism of Surf4 will provide important theoretical basis in the field of cargo receptor mediated secretory pathway, as well as new clues and strategies for diagnosis and treatment of diseases caused by abnormal secretion.