Mechanisms of Translation Regulation During Stress

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ABSTRACT The dynamic regulation of the proteome is critical for cell survival and function. Traditionally, researchers have focused on elucidating the discrete steps of protein synthesis, quality control, and degradation to understand how the proteome is formed and maintained. Yet, a growing body of research suggests communication between translation, quality control, and protein degradation pathways enables the cell to maintain protein homeostasis (proteostasis). Proteostasis collapse is a hallmark of aging and aging-associated neurodegenerative diseases, and alleles of proteostasis genes are associated with a wide range of human genetic diseases. Therefore, understanding the mechanisms that underlie proteostasis holds promise for the identification of novel diagnostic and therapeutic intervention strategies to improve health across the lifespan. My research program will address how protein quality control factors interact and feedback to regulate translation. Our overarching goal is to determine the mechanisms by which protein degradation factors collaborate with the translational machinery to synthesize proteins. We hypothesize that the dynamic regulation of mRNA translation requires protein quality control and degradation activities to prevent catastrophic proteostatic collapse. This hypothesis is supported by the observations that inhibition of the ubiquitin- proteasome system feeds back to (i) inhibit global translation activity, and (ii) impairs the dynamics of RNA- protein (RNP) granules that sequester translationally repressed mRNAs. In the next five years, my research group will evaluate the role of protein quality control and degradation factors in mediating protein synthesis at the levels of translation initiation, elongation, and by facilitating the dynamic assembly and disassembly of RNP granules. To begin to address this problem, we will answer the following questions: (1) Is translation elongation differentially regulated during proteostatic stress? (2) What is the role of the protein quality control machinery in mediating translation initiation and elongation? (3) What is the relationship between translation and RNP granules? (4) What are the molecular mechanisms by which protein quality control and degradation factors drive RNP granule disassembly? We will leverage advanced genome engineering, optogenetics, and live cell imaging strategies to define the mechanisms that regulate mRNA translation in human cells in response to proteostatic stressors. The outcome of this research will be a spatially and temporally defined map of the molecular mechanisms governing mRNA translation during proteostatic stress. The impact of this work will be in contributing to our knowledge of how proteostasis is maintained in eukaryotes and identifying novel treatment approaches for a wide range of human diseases that arise due to loss of proteostasis.