Roles of Rab18 in ER/golgi trafficking

Rab18 在 ER/高尔基体贩运中的作用

基本信息

批准号：
262040-2011
负责人：
Presley, John
金额：
$ 2.91万
依托单位：
McGill University
依托单位国家：
加拿大
项目类别：
Discovery Grants Program - Individual
财政年份：
2011
资助国家：
加拿大
起止时间：
2011-01-01 至 2012-12-31
项目状态：
已结题

来源：
https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=480123
关键词：
Roles Rab18 ER golgi trafficking

项目摘要

Rabs are a family of Ras-related proteins which typically regulate membrane trafficking steps by regulating fusion of transport vesicles with target membranes, by regulating interaction of these transport vesicles with cytoskeleton and by regulating enzymes that modify lipids on the membrane of transport vesicles. There are more than 60 known Rab proteins in humans and many are known to have a specific organellar localization and to regulate a specific transport step. We have a specific interest in Rab18 which is found on the endoplasmic reticulum and lipid droplets. We have found that mutation or siRNA knockdown of Rab18 causes fragmentation of the Golgi apparatus and impairments in the secretory pathway (Dejgaard et al., 2008. J. Cell Sci., 121:2768-81). In a separate ongong study, we have found that an activated mutant of Rab18 induces profuse fusion of lipid droplets which depends on the SNARE proteins syntaxin-5, SNAP23 and VAMP4. Syntaxin-5 is also critical for fusion events in the early secretory pathway, but its regulation is not well understood. In the current application we propose to clarify the essential roles that Rab18 plays in movement of vesicles and cargo between the endoplasmic reticulum and the Golgi apparatus. We hypothesize that Rab18 is functioning in the early secretory pathway in part as a regulator of Syntaxin-5. We also explore the possibility that Rab18 regulates cholesterol homeostasis in the early secretory pathway and that it could regulate motor proteins on transport intermediates that move cargoes between endoplasmic reticulum and Golgi membranes. For these studies we will use a combination of light microscopy, siRNA and biochemical techniques.

Rab 是 Ras 相关蛋白家族，通常通过调节转运囊泡与靶膜的融合、调节这些转运囊泡与细胞骨架的相互作用以及通过调节修饰转运囊泡膜上脂质的酶来调节膜运输步骤。人类中有超过 60 种已知的 Rab 蛋白，其中许多蛋白具有特定的细胞器定位并调节特定的运输步骤。我们对在内质网和脂滴上发现的 Rab18 特别感兴趣。我们发现 Rab18 的突变或 siRNA 敲低会导致高尔基体断裂和分泌途径受损（Dejgaard 等人，2008. J. Cell Sci.，121：2768-81）。在另一项 ongong 研究中，我们发现 Rab18 的激活突变体可诱导脂滴的大量融合，这取决于 SNARE 蛋白 Syntaxin-5、SNAP23 和 VAMP4。 Syntaxin-5 对于早期分泌途径中的融合事件也至关重要，但其调控机制尚不清楚。在当前的应用中，我们建议阐明 Rab18 在内质网和高尔基体之间的囊泡和货物运动中发挥的重要作用。我们假设 Rab18 在早期分泌途径中部分发挥 Syntaxin-5 的调节作用。我们还探讨了 Rab18 调节早期分泌途径中胆固醇稳态的可能性，以及它可以调节在内质网和高尔基膜之间运输货物的运输中间体上的运动蛋白。对于这些研究，我们将结合使用光学显微镜、siRNA 和生化技术。