高尔基体膜蛋白PAQR3参与营养感应与脂代谢稳态调控的机制研究

传统观点认为细胞器高尔基体主要参与了细胞内蛋白的运输，但我们近年的研究发现高尔基体膜蛋白PAQR3能够调控多个关键细胞信号通路，并参与了机体的稳态调控。通过调控Scap-SREBP2向高尔基体转运，PAQR3影响胆固醇合成代谢；通过影响class I PI3K通路，PAQR3具有调控血糖稳态功能；通过调控class III PI3K, PAQR3影响了细胞自噬对于葡萄糖的营养感应。在该项目中，我们将深入研究PAQR3对机体稳态调控的细胞学和生理学机制。基于前期工作的基础，集中研究：（1）PAQR3参与营养感应包括氨基酸和生长因子对于细胞自噬的调控功能；（2）PAQR3通过调控SREBP和PPARalpha通路参与机体脂代谢稳态的调控功能。这些研究不仅能深入揭示高尔基体对于机体代谢稳态的调控作用，并为未来探索新的营养代谢稳态失衡相关疾病的干预提供全新思路。

Traditional views regard Golgi apparatus as a major player in protein trafficking within the cell. However, recent studies from our laboratory have revealed that PAQR3, a Golgi-localized membrane protein, is actively involved in the regulation of multiple signaling pathways and physiological homeostasis. PAQR3 modulates biosynthesis of cholesterol by regulating Golgi accumulation of Scap-SREBP2 complex. PAQR3 regulates insulin signaling and glucose homeostasis by altering the activity of class I PI3K. PAQR3 controls autophagy by modulating class III PI3K under the condition of glucose starvation. We plan to further explore the regulatory functions of PAQR3 on homeostasis of autophagy and lipid metabolism. Based on our preliminary results, we will focus on two specific aims. (1) To elucidate PAQR3 regulation on nutrient-mediated regulation of autophagy via amino acids and growth factors. (2) To investigate PAQR3 regulation on lipid homeostasis via modulating the functions of SREBP and PPARalpha. Studies on these key scientific questions will not only strengthen our understanding about how Golgi apparatus is implicated in controlling homeostasis and metabolism, but also pave the way for future intervention and therapy for diseases caused by dysregulation of nutrition and metabolism.