Translational control by nutrients

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The ability to adapt to environmental challenges is critical for cellular and organismal function. A frequent challenge is dehydration which increases osmotic pressure on the cells causing water loss and cell shrinkage. Cells respond by accumulating organic osmolytes to accommodate decreases in cell volume and ionic strength in a process called osmoadaptation. This cellular stress response is critical for survival of all organisms and tissues. Defects in osmoadaptation induce a pro-inflammatory program that decreases cell survival and has implications for multiple pathologies, including inflammatory bowel disease, diabetes, cancer and dry eye syndrome. Diabetes associated hyperglycemic hyperosmolar syndrome (HHS) is life threatening. It is therefore important to understand the molecular mechanisms of osmoadaptation. Our application focuses on the regulation of protein synthesis during osmoadaptation, a critical process that is poorly understood. The overall goal of this proposal is to develop a mechanistic, transcriptome-wide understanding of translation regulation during osmoadaptation that will lead to development of therapeutics of diseases that cause decreased tissue osmotolerance. We will examine the function of key regulators, including the amino transporter SNAT2 for establishing osmoadaptive mRNA translation programs using Human Corneal Epithelial Cells (HCEs). Corneal Epithelial cells are the cells in the eye that develop the pathology of dry eye syndrome in diabetes. To develop a mechanistic, transcriptome-wide understanding of translation regulation during osmoadaptation we characterize the translation landscape during osmoadaptation and define the regulatory RNA features that control the changes in mRNA translation (Aim 1). We then focus on the interplay between translation regulation, amino acid homeostasis and liquid-liquid phase separation (LLPS) of RNA binding proteins (RBPs) during osmoadaptation and delineate how mTOR and SNAT2 activities affect the translation landscape in response to hyperosmotic stress (Aim 2). Finally, we examine the function of RBPs that link LLPS and translation regulation, by determining RNA binding patterns and LLPS for specific RBPs during osmoadaptation (Aim 3).