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体内显然很重要，它们提供了一系列生命所必需的功能。所有这些组织的成分都是在我们体内特殊类型的细胞中形成的，然后这些细胞将它们释放或分泌到细胞外，在细胞外，各个成分组合成复杂的网络，最终形成特定组织的物理结构。分泌的成分通常是在细胞分泌之前和之后经历广泛修饰的大蛋白质。分泌的蛋白质是在细胞内一个叫做内质网的特殊区域合成的，在这个区域，许多蛋白质经过了广泛的修饰，通常包括在糖基化过程中添加糖链。然后，蛋白质以小的球形包运送到另一个称为高尔基体的隔室，在那里进行进一步的糖基化和添加的糖链的加工。修饰后的蛋白质在高尔基体中被包装成不同的囊泡，运送到细胞表面并从细胞中释放出来。许多人类疾病影响皮肤和骨骼的形成或维持，此外，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叫做老年病，它会导致皮肤松弛、皱纹和骨质疏松，这些症状与衰老过程中出现的症状相似。氧化石墨烯的原因是编码高尔基体蛋白GORAB的基因突变。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。我们已经获得了初步证据，表明GORAB对于高尔基复合体的囊泡运输和通过该隔室转运的货物蛋白上的糖链的正确加工是重要的。因此，我们认为氧化石墨烯是由构成皮肤和骨骼的蛋白质的缺陷修饰引起的，从而导致在这些组织中观察到的病理效应。本文描述的工作旨在确定GORAB在高尔基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，重点是构成皮肤的那些蛋白。这项工作不仅对确定氧化石墨烯的机制很重要，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是如何变化的。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.