Fundamental connections between protein synthesis and carbohydrate metabolism: eIF4A regulation

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The information carried in the genes from living cells is decoded to produce chains of different amino acids called proteins that dictate the identity and function of that cell. Proteins represent one of the building blocks of all life, catalyzing most of the biochemical reactions as well as serving numerous structural and regulatory roles. An intermediate between the gene and the protein is the messenger RNA (mRNA). In eukaryotic cells (animals, plants and fungi), genes have been segregated into the nucleus away from the machinery involved in protein synthesis allowing independent regulation of mRNA and protein production. The 'translation' of the code contained in the mRNA is a complicated process that is highly similar across eukaryotic cells. All organisms need to be able to adapt to changes in their external environment. This adaptation involves changing the levels of individual proteins within cells. Hence, in response to stresses such as increases in temperature or starvation for certain nutrients, cells rapidly halt the process of protein synthesis to allow a switch to a stress specific protein production pathway. We are studying this regulation of translation using the simple eukaryote, brewer's yeast, as a model organism. Sugars are essential for life. Fundamentally, the breakdown of sugars provides the chemical energy that drives most other processes in living cells. The sugar, glucose, is used as the major source of energy in most living systems from bacteria to humans. For instance, as simple eukaryotic micro-organisms, yeast prefer to grow on glucose as a sugar source. One of the most dramatic decreases in protein production observed in response to stress in yeast occurs rapidly after the depletion of glucose from the growth media. We have recently discovered that a specific and critical translation factor dissociates from the translation machinery after glucose starvation. This factor is called the eukaryotic translation initiation factor 4A (eIF4A). eIF4A is an example of a class of proteins called helicases. These proteins can unwind DNA and RNA molecules, and eIF4A can unwind sections of the mRNA. This is thought to give the translation machinery access and promote the overall transit or 'scanning' of this machinery along the mRNA in search of an initiation site.Therefore in this proposal, we will study how the removal of glucose from yeast cells causes a loss of eIF4A from translating mRNAs. We seek to answer questions relating to what causes this reduction in the level of eIF4A associated with the translation machinery, how important this eIF4A loss is in the inhibition of protein production and whether mRNAs that continue to be translated are bound by eIF4A or other helicases. This project is important because it brings together two pathways that are fundamental to living systems these are the energy generating system and the protein production system. A detailed characterisation of this mechanism in brewer's yeast will facilitate the longer term investigation in other organisms. Should such a pathway of translation control be present in other organisms (possibly activated by different stresses) then it is likely to be very important for the physiology of that organism. Should the pathway prove to be fungal-specific then it might represent a new target for drug design to combat human pathogenic fungi.