Translating the ubiquitin code in mitotic cells

受调控的基因表达确保细胞正确选择其功能所需的基因编码蛋白质成分。然而，细胞也需要一种方法来去除蛋白质，一旦它们不再需要，或者如果它们是有缺陷的。细胞对不需要的蛋白质的‘消化’被称为蛋白分解，在称为蛋白酶体的亚细胞机器中非常迅速地发生。蛋白质通过特定的标记进入蛋白酶体，这种蛋白被称为泛素(Ubiquitin)，它是一种无处不在的小蛋白的多个副本，形成的链可以被蛋白酶体盖上的受体识别。泛素标签还调节其他与蛋白质降解无关的功能，我们对不同类型的泛素链如何控制不同结果的了解日益增长，从而产生了泛素密码的概念。人类基因组的很大一部分编码泛素-蛋白酶体系统(UPS)的组成部分，因为几乎所有的细胞过程都需要泛素介导的调控。例如，在细胞分裂(有丝分裂)的调节中，在准确的时间和地点精确地破坏几个关键成分，驱动整个过程。UPS的复杂性意味着泛素链有许多种，其中一些在将靶向蛋白质定向到蛋白酶体方面比其他一些更好。换句话说，不同蛋白质的蛋白质分解发生的速率不同，这取决于它们携带的泛素链的类型。我们仍然不太清楚泛素密码的这一部分，以及它是如何被翻译成蛋白质分解的。这一建议侧重于有丝分裂的两个关键调节因子，称为极光激酶(A和B)的蛋白质分解。两者都是相同的UPS途径的靶标，但在有丝分裂结束时，它们被破坏的速度非常不同。它们最终消失的时间上的差异对于有丝分裂退出时正确的事件顺序至关重要。我们的初步研究表明，不同的蛋白质降解速率是由于Aurora A和Aurora B上组装的泛素密码的不同。我们建议对应用于Aurora激酶的泛素密码进行详细研究，以了解泛素密码中引导蛋白酶体快速破坏的部分。我们将利用我们的新知识来设计试剂，这些试剂可以通过利用UPS来人工操纵极光蛋白激酶的细胞水平，或它们所结合的其他细胞目标。目前正在开发的新一代靶向疗法(称为蛋白质靶向嵌合体，或PROTACS)将在未来提供靶向错误或在错误时间和地点表达的细胞蛋白质的能力，就像疾病中经常出现的情况一样。了解泛素代码将有助于这些工具的未来设计。

Regulated gene expression ensures that cells make the correct selection of genetically encoded protein components required for their function. However, cells also require a method to get rid of proteins once they are no longer required, or if they are faulty. Cellular 'digestion' of unwanted proteins is called proteolysis, and occurs very rapidly inside subcellular machines called proteasomes. Proteins are directed into proteasomes by specific tagging with multiple copies of a small ubiquitous protein known as 'ubiquitin', which forms chains that can be recognized by receptors on the lid of the proteasome. Ubiquitin tags also mediate other functions unrelated to proteolysis, and our growing knowledge of how different types of ubiquitin chain direct different outcomes has given rise to the concept of a 'ubiquitin code'.A large fraction of the human genome encodes components of the Ubiquitin-Proteasome System (UPS), because almost all cellular processes require ubiquitin-mediated control. For example in regulation of cell division (mitosis) precise destruction of several key components, at exactly the right time and place, drives the whole process. The complexity of the UPS means that ubiquitin chains come in many varieties, and some are better than others at directing targeted proteins to the proteasome. In other words, the proteolysis of different proteins happens at different rates, depending on what type of ubiquitin chain they carry.We still don't know very much about this part of the ubiquitin code, and how it is translated into proteolysis.This proposal focuses on proteolysis of two key regulators of mitosis, called the Aurora kinases (A and B). Both are targeted by the same UPS pathway, but they are destroyed at very different rates at the end of mitosis. The resulting difference in timing of their eventual disappearance is critical to the correct sequence of events at mitotic exit. Our preliminary studies indicate that the different rates of proteolysis arise from differences in the ubiquitin code assembled on Aurora A versus Aurora B. We propose a detailed study of the ubiquitin code applied to Aurora kinases, to understand the part of the ubiquitin code that directs rapid destruction at the proteasome. We will use our new knowledge to design reagents that can be used to artificially manipulate cellular levels of Aurora kinases, or of other cellular targets to which they bind, by harnessing the UPS. A new generation of targeted therapies currently in development (called Protein Targeting Chimeras, or PROTACS) will in the future deliver the ability to target cellular proteins that are faulty, or expressed in the wrong time and place, as is often the case in disease. Understanding the ubiquitin code will assist the future design of these tools.