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Ubiquitination as a transient modification in regulated protein trafficking

泛素化作为受调控蛋白质运输的瞬时修饰

基本信息

批准号：
MR/J000221/1
负责人：
Nia Bryant
金额：
$ 54.3万
依托单位：
University of Glasgow
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2012
资助国家：
英国
起止时间：
2012 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FJ000221%2F1
关键词：
Ubiquitination transient modification regulated protein

项目摘要

Proteins are moved from one part of the cell to another by 'protein trafficking'. This is achieved through recognition of information contained within, or attached to, the cargo protein by molecular machinery that specifies delivery from one location to another. The function of many cells in the body require proteins to change location under different circumstances, e.g. in response to an external signal, or during different stages of development. This is achieved through regulated protein trafficking, a process central to many physiological processes including hormone secretion, antigen presentation, cell division and whole body glucose homeostasis. Protein trafficking defects have been identified in many disease states where these processes are perturbed. These include cancer, autoimmune diseases and diabetes. Understanding regulated protein traffic will therefore better arm us against these diseases.In many examples of regulated trafficking, the signals that specify which trafficking step a protein is sorted into are often added to the protein in response to an external cue and can then be rapidly removed when no longer required. One example of this is the addition of the small protein ubiquitin to other proteins. The addition of ubiquitin (ubiquitination) has long been known to target proteins for degradation by delivering them into a pathway which leads to the lysosome - a compartment within the cell which functions to degrade proteins. E.g. many cell surface receptors that transmit information from outside to inside the cell are ubiquitinated following stimulation. This leads to their internalization and lysosomal delivery and serves to attenuate signaling events. The activity of de-ubiquitinating enzymes (DUBs) that remove ubiquitin has been shown to rescue some receptors from this pathway allowing recycling back to the cell surface, allowing the cell to fine-tune signaling responses. As well as signaling delivery of proteins from the cell surface to the lysosome, ubiquitin can also direct newly synthesized proteins there from the biosynthetic pathway.This proposal is directed towards understanding the role of ubiquitin in regulated protein traffic, using sorting of the glucose transporter GLUT4 as a paradigm. Insulin stimulates glucose transport into fat and muscle cells by promoting delivery of a glucose transport protein (GLUT4) from a specialized internal store to the cell surface. In this way insulin increases the rate of glucose transport into fat and muscle, and thus controls whole body glucose homeostasis. Insulin-dependent delivery of GLUT4 to the cell surface is an example of regulated membrane traffic and is impaired in the disease states of insulin-resistance and Type-2 diabetes. We have recently demonstrated a role for ubiquitin in the delivery of GLUT4 into its specialized internal store. We have also identified a role for a DUB in GLUT4 traffic. We now aim to test our working model that describes how ubiqutination of GLUT4 sorts it into a lysosomal trafficking pathway. We propose that deubiquitination of GLUT4 then rescues the transporter from lysosomal degradation and that this deubiquitination is critical for sorting GLUT4 into the store from where it is mobilized to the cell surface in response to insulin. Our working model represents the first example of a DUB rescuing a ubiquitinated protein from lysosomal delivery via the biosynthetic pathway and thus introduces a new paradigm into the field. This study also has the potential to serve as a model for other regulated trafficking systems such as those mentioned above, whose dysfunction can lead to disease states and hence our work may lead to therapeutic interventions for a wide range of diseases including cancer and diabetes. In addition, many parasites and viruses hijack the host cell's trafficking machinery and therefore understanding this process may arm us in battle against such infectious agents.

蛋白质通过“蛋白质运输”从细胞的一个部分转移到另一个部分。这是通过识别包含在货物蛋白内或附着在货物蛋白上的信息来实现的，所述货物蛋白通过分子机制指定从一个位置到另一个位置的递送。身体中许多细胞的功能需要蛋白质在不同的情况下改变位置，例如响应外部信号，或在不同的发育阶段。这是通过调节蛋白质运输来实现的，蛋白质运输是许多生理过程的中心过程，包括激素分泌、抗原呈递、细胞分裂和全身葡萄糖稳态。蛋白质运输缺陷已被确定在许多疾病状态，这些过程受到干扰。这些疾病包括癌症、自身免疫性疾病和糖尿病。因此，了解受调控的蛋白质运输将更好地帮助我们对抗这些疾病。在许多受调控的运输的例子中，指定蛋白质被分选到哪个运输步骤的信号通常是响应外部提示而添加到蛋白质中的，然后在不再需要时可以迅速去除。其中一个例子是将小蛋白泛素添加到其他蛋白质中。长期以来，已知添加泛素（泛素化）通过将蛋白质递送到导致溶酶体的途径中来靶向蛋白质以进行降解-溶酶体是细胞内具有降解蛋白质功能的隔室。例如，许多从细胞外向细胞内传递信息的细胞表面受体在刺激后被泛素化。这导致它们的内化和溶酶体递送，并用于减弱信号传导事件。去除泛素的去泛素化酶（DUB）的活性已被证明可以从该途径中拯救一些受体，从而允许再循环回到细胞表面，允许细胞微调信号传导反应。除了将蛋白质从细胞表面传递到溶酶体的信号传递外，泛素还可以将新合成的蛋白质从生物合成途径引导到溶酶体。胰岛素通过促进葡萄糖转运蛋白（GLUT 4）从专门的内部储存到细胞表面的递送来刺激葡萄糖转运到脂肪和肌肉细胞中。通过这种方式，胰岛素增加葡萄糖转运到脂肪和肌肉中的速率，从而控制全身葡萄糖稳态。GLUT 4向细胞表面的胰岛素依赖性递送是受调节的膜运输的一个实例，并且在胰岛素抵抗和2型糖尿病的疾病状态中受损。我们最近已经证明了泛素在将GLUT 4运送到其专门的内部储存中的作用。我们还确定了DUB在GLUT 4流量中的作用。我们现在的目标是测试我们的工作模型，该模型描述了GLUT 4的泛素化如何将其分类为溶酶体运输途径。我们提出，GLUT 4的去泛素化，然后拯救从溶酶体降解的转运蛋白，这种去泛素化是至关重要的GLUT 4从哪里被动员到细胞表面响应胰岛素的存储。我们的工作模型代表了DUB通过生物合成途径从溶酶体递送中拯救泛素化蛋白的第一个例子，从而为该领域引入了一个新的范式。这项研究也有可能作为其他受管制贩运系统的模型，例如上述那些系统，其功能障碍可能导致疾病状态，因此我们的工作可能导致对包括癌症和糖尿病在内的广泛疾病的治疗干预。此外，许多寄生虫和病毒劫持宿主细胞的运输机制，因此了解这一过程可能会帮助我们对抗这些传染性病原体。