Ligand modulation of the Integrated stress response

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Proteins perform nearly all functions in cells needed for life. Each protein is made from amino acids linked in chains and which folded into unique structures that enable each protein to fulfil individual roles in the body. The instructions required to make each protein correctly are determined by the DNA sequences of our genes in the genome. Called protein synthesis, it is critical that the instructions are decoded accurately at the right place and the right time. This enables organ and cell-specific proteins to only be made in those tissues and cells where they are required. It is also important that cells can both control and rapidly change which proteins they make at any one time, so that organisms can respond rapidly to changes around them. Examples include: 1) changes in protein synthesis in brain cells help to form memories; 2) during early pregnancy to ensure that embryos develop the right tissues in the right places; 3) when people are infected with viruses; and 4) when people suffer from diseases such as obesity or cancer.Protein synthesis occurs within relatively large and complex molecular machines called ribosomes that decode instructions relayed from the genome. This is made possible by the action of 'helpers' called protein synthesis factors and adapters called transfer RNAs (tRNAs). Together they bring the necessary amino acids together with gene instructions to ensure the correct proteins are made at the right time and place. This proposal concerns how protein synthesis is regulated by stress in a process widely called the integrated stress response (ISR). The protein synthesis factor called eIF2 brings the starting tRNA (tRNAi) to the ribosome to begin making every protein. eIF2 is known to be controlled by the ISR. When this control is out of balance it can contribute to common diseases such as cancers, diabetes, heart disease and a range of neurodegenerative conditions. We know the central element of the ISR is a reaction by which eIF2 can be modified response to stress by protein enzymes called protein kinases and that the modified version is switched off. A second enzyme called a phosphatase can switch eIF2 back on again to reset the control switch. So while it appears we understand this regulatory circuit, we now know that eIF2 interacts with many other protein synthesis factors rather than being found free in cells. How the regulatory kinases and phosphatases can access eIF2 when it is also interacting with these different other proteins is not known. Understanding this will inform how rapidly eIF2 can be switched between 'on' and 'off' states and identify which forms of eIF2 are resistant to change. Current models of how this works assume only free eIF2 can be modified. Our preliminary data questions this assumption and provides a strong basis to evaluate which forms of eIF2 can be regulated. We propose here a series of biochemical experiments to address which eIF2-containing complexes can be switched on and off in the ISR. The knowledge gained in understanding these reactions and interactions could help explain different responses to stress in different tissues and may help inform the design of better therapeutics for a wide range of conditions.