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，一旦蛋白质不再需要，或者如果它们有缺陷，就可以摆脱它们。细胞对不需要的蛋白质的“消化”被称为蛋白质水解，在被称为蛋白酶体的亚细胞机器中迅速发生。蛋白质通过一种被称为“泛素”的小的无所不在的蛋白质的多个拷贝的特定标记被引导到蛋白酶体中，泛素形成的链可以被蛋白酶体盖子上的受体识别。泛素标签也介导其他与蛋白质水解无关的功能，我们对不同类型的泛素链如何指导不同结果的了解不断增加，这就产生了“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控制。例如，在细胞分裂（有丝分裂）的调控中，精确地破坏几个关键成分，在正确的时间和地点，驱动整个过程。UPS的复杂性意味着泛素链有多种变体，其中一些在将目标蛋白质导向蛋白酶体方面比其他的更好。换句话说，不同蛋白质的蛋白水解速率不同，这取决于它们携带的泛素链的类型。我们仍然对泛素编码的这一部分知之甚少，也不知道它是如何转化为蛋白质水解的。该建议侧重于有丝分裂的两个关键调节因子的蛋白水解，称为极光激酶（A和B）。两者都被相同的UPS通路靶向，但它们在有丝分裂结束时以非常不同的速率被破坏。它们最终消失的时间差异对有丝分裂结束时正确的事件顺序至关重要。我们的初步研究表明，不同的蛋白质水解速率是由Aurora A和Aurora b上组装的泛素代码的差异引起的。我们建议对应用于Aurora激酶的泛素代码进行详细研究，以了解泛素代码中指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来人为地操纵极光激酶的细胞水平，或者它们结合的其他细胞靶标。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）将在未来提供靶向有缺陷的细胞蛋白质的能力，或者在错误的时间和地点表达，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.