Novel functions of importin-alpha in RNA metabolism and the stress response

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In eukaryotic cells, the importin-a protein family (here referred to as importin-a) contributes to multiple aspects of cell physiology. Aside from nuclear transport, family members are implicated in additional vital biological processes. Recent studies suggest that importin-a has new functions in RNA metabolism and the stress response. Thus, we demonstrated that importin-a1 binds poly(A)-RNA. We also showed that multiple members of the importin-a family associate with cytoplasmic stress granules (SGs). How importin-a proteins contribute to these crucial cellular activities is not well understood. Our research program will address these central biological questions.***SHORT-TERM OBJECTIVES. We will characterize novel biological functions of the importin-a protein family as they relate to RNA metabolism and the stress response.***LONG-TERM GOALS. We will (i) define the network consisting of importin-a proteins and their interactors, and (ii) determine the mechanisms through which this network controls a set of diverse biological processes that ultimately regulate cell fate. Our research will provide new insights into the roles of nuclear transport factors as multifunctional components that regulate different cellular activities.***HYPOTHESES. Based on our previous studies, we propose that importin-a regulates fundamental aspects of (1) RNA metabolism, and (2) the cellular stress response.***SPECIFIC AIMS. To test these hypotheses, we will: ***(1) Characterize the interaction of importin-a proteins with RNA under normal and stress conditions. ***(2) Define the mechanisms through which importin-a family members regulate SG biogenesis and impact cell survival in the presence or absence of stress. ***Based on results we recently obtained, our research program takes a novel and exciting direction that explores unexpected and mostly undefined properties of the importin-a family. In particular, the link between nuclear transport factors and RNA metabolism has only recently emerged and is to a large extent not understood. As well, the mechanisms through which importin-a controls the formation of SGs have yet to be determined. These are important biological processes relevant to all eukaryotic cells. Accordingly, the insights generated by us will be critical to understand the role of importin-a as key regulator of cellular homeostasis. We will examine these questions in a rigorous fashion by applying state-of-the-art methods in RNA-profiling, cell imaging, quantitative image analyses and advanced techniques in protein analysis.**