Translating the ubiquitin code in mitotic cells

点击翻译按钮获取中文摘要

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.