Dissecting the function of GORAB, the protein mutated in Geroderma osteodysplastica

皮肤，骨骼，软骨和结缔组织在我们的身体显然是重要的，提供了一系列的功能是必不可少的生命。所有这些组织的组成部分都是在我们体内的特殊类型的细胞内制造的，然后这些细胞将它们释放或分泌到细胞外，在细胞外，各个组成部分组装形成复杂的网络，最终产生特定组织的物理结构。分泌的组分通常是大的蛋白质，其在从细胞分泌之前和之后经历广泛的修饰。分泌的蛋白质在细胞内称为内质网的特定隔室中合成，其中许多蛋白质经历广泛的修饰，通常涉及在称为糖基化的过程中添加糖链。然后蛋白质以小的球形包运输到另一个称为高尔基体的隔室，在那里发生进一步的糖基化和添加糖链的加工。然后，修饰的蛋白质在高尔基体处包装成不同的囊泡，用于递送到细胞表面并从细胞释放。许多人类疾病会影响皮肤和骨骼的形成或维持，而且，众所周知，随着人们年龄的增长，这两种组织都会退化。一种罕见的遗传性疾病，称为骨质增生症，会导致皮肤松弛，骨质疏松，症状类似于衰老。GO的原因是一个基因的突变，该基因编码一种称为GORAB的高尔基体蛋白。GORAB的功能尚不清楚，因此我们不了解GO的症状是如何产生的。我们已经获得的初步证据表明，GORAB是重要的囊泡运输在高尔基复合体和正确的处理货物蛋白质上的糖链过境通过这个车厢。因此，我们认为GO是由构成皮肤和骨骼的蛋白质的缺陷修饰引起的，导致在这些组织中观察到的病理效应。这里描述的工作旨在确定GORAB在高尔基体囊泡运输中的精确功能，然后确定GORAB的丢失如何影响分泌蛋白的修饰，重点是那些组成皮肤的蛋白。这项工作不仅对确定GO的机制很重要，而且对我们更普遍地理解货物修饰具有更广泛的意义，这对所有细胞都至关重要。此外，研究结果将告诉我们皮肤是如何组装的，以及皮肤在疾病中以及在正常衰老过程中如何变化。最后，这项工作也与我们对组织再生和伤口修复等过程的理解有关。

Skin, bone, cartilage and connective tissues in our body are clearly important, providing a range of functions that are essential for life. The components of all of these tissues are made inside special types of cells in our body, which then release, or secrete, them outside the cell, upon which the individual components assemble to form complex networks that ultimately generate the physical structure of the particular tissue. The secreted components are typically large proteins that undergo extensive modifications prior to and after their secretion from the cell. The secreted proteins are synthesized in a particular compartment inside the cell called the endoplasmic reticulum, where many undergo extensive modification, commonly involving the addition of linked chains of sugars in a process termed glycosylation. Proteins are then transported in small spherical packets to another compartment called the Golgi apparatus, where further glycosylation and processing of the added sugar chains occurs. The modified proteins are then packaged at the Golgi apparatus into different vesicles for delivery to the cell surface and release from the cell. Many human diseases affect the formation or maintenance of the skin and bones, and moreover, it is well known that both tissues degenerate as people get older. A rare genetic disorder called Geroderma osteodysplastica causes loose, wrinkly skin and osteoporosis, symptoms similar to those seen in ageing. The cause of GO is mutation of a gene that encodes for a Golgi apparatus protein called GORAB. The function of GORAB is not known, and consequently we do not understand how the symptoms of GO are brought about. We have obtained preliminary evidence that GORAB is important for vesicle transport at the Golgi complex and for the correct processing of sugar chains on cargo proteins transiting through this compartment. Hence, we propose that GO is caused by defective modification of proteins that make up the skin and bone, leading to the pathological effects that are observed in these tissues. The work described here aims to determine the precise function of GORAB in Golgi vesicle transport, and then to determine how the loss of GORAB affects modification of secreted proteins, focusing on those that make up the skin. The work will not only be important for determining the mechanisms of GO, but have more widespread significance for our understanding of cargo modification more generally, which is of fundamental importance to all cells. Moreover, the results will inform us of how the skin is assembled, and how the skin changes both in disease but also likely during the normal ageing process. Finally, the work also has relevance to our understanding of processes such as tissue regeneration and wound repair.