Coordination of membrane traffic in the early secretory pathway

早期分泌途径中膜运输的协调

• 批准号: BB/S014799/1
• 负责人: Martin Lowe
• 金额: $ 59.05万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FS014799%2F1
• 关键词: Coordination; membrane; traffic; early; secretory

Proteins and lipids are the major building blocks of cells, and as such are constantly produced within the cells or our body. The constant synthesis of these molecules is required for the growth and healthy maintenance of our tissues. Approximately one third of all proteins and practically all lipids are made in a cell compartment called the endoplasmic reticulum, from where most proteins and lipids are further transported to downstream compartments in specialized carriers called transport vesicles. This transport occurs along the secretory pathway, which delivers the proteins and many of the lipids to their final destination in the cell, or in some cases the molecules are released from the cell by secretion, as is the case for hormones, neurotransmitters, extracellular proteins that make up our skin and bone, and cholesterol-rich particles that circulate in our bloodstream. A major gatekeeping step in the secretory pathway is the exit of cargo proteins and lipids from the endoplasmic reticulum, a process mediated by specialized machinery called COPII, which acts together with accessory factors to ensure cargo is released in an efficient and properly controlled manner into carriers destined for the next compartment of the secretory pathway. This forward transport of cargo must also be balanced with transport in the reverse direction, which acts to recycle key factors and is mediated by a different machinery, called COPI. The mechanisms by which forward and backward transport are coordinated, which is vital for secretory pathway function, are unknown. Moreover, although we know defective secretory cargo transport negatively impacts upon cell viability and human health, the underlying mechanisms remain poorly defined. This proposal focuses on a protein called Scyl1, whose mutation causes CALFAN syndrome in humans, a disorder that affects the nervous system, liver and skeleton. Presently we have only a poor understanding of Scyll1 function. We have obtained preliminary evidence that Scyl1 functions in conjunction with COPII, and that loss of Scyl1 disrupts cargo protein transport in the secretory pathway. These results point to a new role for Scyl1 in controlling exit of cargo proteins from the endoplasmic reticulum. Moreover, since Scyl1 is unique in its ability to bind to both COPII and COPI, it is a prime candidate for a factor coordinating forward and backward transport in the secretory pathway. Finally, because our preliminary results indicate that defective secretory cargo transport upon loss of Scyl1 causes induction of cell stress, investigating the underlying mechanisms of stress induction and its consequences will reveal how defective trafficking causes loss of cell viability, which is important for our understanding of human health. The work will not only be important for determining the mechanisms of CALFAN syndrome, but will have significance for our understanding of secretory cargo transport more generally, which is of fundamental importance to all cells.

蛋白质和脂质是细胞的主要组成部分，因此在细胞或我们的体内不断产生。这些分子的不断合成是我们组织的生长和健康维持所必需的。大约三分之一的蛋白质和几乎所有的脂质都是在称为内质网的细胞区室中产生的，大多数蛋白质和脂质从这里被进一步运输到称为运输囊泡的特殊载体中的下游区室。这种运输沿着分泌途径发生，该途径将蛋白质和许多脂质输送到细胞中的最终目的地，或者在某些情况下，分子通过分泌从细胞中释放出来，例如激素、神经递质、构成皮肤和骨骼的细胞外蛋白质以及在我们血液中循环的富含胆固醇的颗粒。分泌途径中的一个主要把关步骤是货物蛋白和脂质从内质网中退出，这是一个由称为 COPII 的专门机制介导的过程，它与辅助因子一起作用，以确保货物以有效且适当控制的方式释放到运往分泌途径下一个区室的载体中。货物的正向运输还必须与反向运输相平衡，反向运输的作用是回收关键因素，并由称为 COPI 的不同机制进行调节。对于分泌途径功能至关重要的向前和向后运输的协调机制尚不清楚。此外，尽管我们知道有缺陷的分泌货物运输会对细胞活力和人类健康产生负面影响，但其潜在机制仍不清楚。该提案重点关注一种名为 Scyl1 的蛋白质，该蛋白质的突变会导致人类出现 CALFAN 综合征，这是一种影响神经系统、肝脏和骨骼的疾病。目前我们对Scyll1函数的了解还很有限。我们已经获得了初步证据，表明 Scyl1 与 COPII 协同发挥作用，并且 Scyl1 的丢失会破坏分泌途径中的货物蛋白运输。这些结果表明 Scyl1 在控制货物蛋白从内质网退出方面发挥着新作用。此外，由于 Scyl1 具有与 COPII 和 COPI 结合的独特能力，因此它是协调分泌途径中向前和向后运输的因子的主要候选者。最后，由于我们的初步结果表明，Scyl1 丢失后分泌性货物运输缺陷会导致细胞应激的诱导，因此研究应激诱导的潜在机制及其后果将揭示运输缺陷如何导致细胞活力丧失，这对于我们了解人类健康非常重要。这项工作不仅对于确定 CALFAN 综合征的机制很重要，而且对于我们更广泛地理解分泌性货物运输具有重要意义，这对所有细胞都至关重要。

项目成果

GOLPH3 keeps the Golgi residents at home.

• DOI: 10.1083/jcb.202108147
• 发表时间: 2021-10-04
• 期刊: The Journal of cell biology
• 作者: Lowe M

The inositol 5-phosphatase INPP5B regulates B cell receptor clustering and signaling.

• DOI: 10.1083/jcb.202112018
• 发表时间: 2022-09-05
• 期刊: The Journal of cell biology