Dissecting the roles of ZFPL1 and GMAP210 in Golgi biogenesis and membrane traffic

所有来自动物、植物和真菌的细胞都由不同的隔间组成，每个隔间都有独特的组成和特定的功能。物质在这些隔室或细胞器之间以膜包裹的形式运输，称为囊泡。这一过程被称为膜运输，是细胞和生物体作为一个整体正常运作所必需的。例如，荷尔蒙、抗体、神经递质以及皮肤、软骨和骨骼的主要成分通过与细胞表面融合的囊泡从细胞中释放出来，而生长因子和死亡细胞则通过从细胞表面吸收的囊泡从血液中移除。细胞中的一个主要隔室是高尔基体，这是一组扁平的膜袋，称为池子，它们相互层叠，形成堆叠。高尔基体有两个主要功能：它负责修饰存在于蛋白质和脂类上的糖链；以及将这些分子包装成运输小泡，以便运送到细胞表面或细胞内的其他隔室。蛋白质的适当修饰和传递是至关重要的。高尔基体功能的缺陷和膜的运输通常是导致许多人类疾病的原因。此外，膜运输机械的部件，包括高尔基体的部件，被某些细菌和病毒劫持，使这些病原体能够复制和/或避免被免疫系统检测。因此，重要的是我们要了解高尔基体如何在分子水平上发挥作用。所有的膜运输步骤都涉及一个称为系绳的过程，这是运输载体与其目的地隔间的初始连接。细胞中有许多系留因子，包括高尔基体中的一系列相关系留蛋白。其中一种名为GMAP210的蛋白质的突变最近被证明会导致人类的一种致命的骨骼疾病。发生这种情况的机制以及GMAP210和其他拴系因子如何在健康细胞中发挥作用的细节尚不清楚。这项建议的目的是确定GMAP210的功能是如何调控的，重点是它与我们最近发现的高尔基体的另一种蛋白质的关系。这项工作将告诉我们，拴系的基本过程是如何在细胞内发生的，以及这一过程中的缺陷如何导致人类的骨骼疾病，并可能导致其他类型的疾病。

All cells from animals, plants and fungi are made up of different compartments, each with a unique composition and specific functions. Material is transported between these compartments, or organelles, in membrane-bound packets called vesicles. This process, referred to as membrane traffic, is required for the correct functioning of cells, and organisms as a whole. For example hormones, antibodies, neurotransmitters, and the major components of skin, cartilage and bone are released from cells in vesicles that fuse with the cell surface, while growth factors and dead cells are removed from the bloodstream in vesicles that are taken up from the cell surface. One of the major compartments in cells is the Golgi apparatus, a collection of flattened membrane sacks called cisternae that are layered on top of each other to form stacks. The Golgi apparatus has two major functions: it is responsible for modifying sugar chains present on proteins and lipids; and the packaging of these molecules into transport vesicles for delivery to the cell surface or other compartments in the cell. Proper modification and delivery of proteins is of fundamental importance. Defects in Golgi function, and membrane traffic in general, are responsible for a number of human diseases. Furthermore, components of the membrane traffic machinery, including those at the Golgi apparatus, are hijacked by certain bacteria and viruses, allowing these pathogens to replicate and/or avoid detection by the immune system. It is therefore important we understand how the Golgi apparatus functions at the molecular level. All membrane traffic steps involve a process called tethering, which is the initial attachment of the transport carrier to its destination compartment. There are many tethering factors in cells, including a family of related tethering proteins at the Golgi apparatus. Mutation of one of these proteins called GMAP210 has recently been shown to cause a lethal skeletal disease in humans. The mechanisms by which occurs are poorly understood, as are the details of how GMAP210 and other tethering factors work in healthy cells. The aim of this proposal is to determine how GMAP210 function is regulated, focussing on its association with another protein of the Golgi apparatus that we have recently identified. This work will inform us of how the fundamental process of tethering takes place inside cells, and how defects in this process can lead to skeletal and possibly other types of disease in humans.