Novel functions of nuclear transport factors in cellular homeostasis

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Nuclear transport factors participate in different aspects of eukaryotic cell physiology. Their contributions range from cell growth to scaling, aging and death. Recent studies suggest new functions for nuclear transport factors that are related to RNA homeostasis and the stress response. In support of this model, our group demonstrated that importin-a1 binds polyA-RNA. We further showed that all importin-a sub-families associate with cytoplasmic stress granules. Stress granules contain a diverse set of proteins and RNAs. As membraneless compartments, they assemble through phase separation. Our laboratory also established links between nuclear transport factors and cytoplasmic granules that accumulate damaged RNA. These unique compartments are not stress granules. To date, clear experimental evidence shows that nuclear transport factors are essential regulators of cell compartments that form by phase separation. Specifically, nuclear transport factors have emerged as pillars of a multi-layered quality control network that scrutinizes RNA granules in the cytoplasm. The underlying molecular mechanisms are poorly understood. Our research program will address these central biological questions. To this end, we have established three independent in vitro and in vivo model systems of increasing complexity. SHORT-TERM OBJECTIVES. We will characterize novel biological functions of nuclear transport factors that are linked to protein and RNA homeostasis. LONG-TERM GOALS. Our research program will (i) define the protein and RNA quality control network that is driven by nuclear transport factors, and (ii) dissect the mechanisms through which this network modulates biological processes that ultimately determine cell fate. HYPOTHESES. Based on our ongoing studies, we propose that (1) nuclear transport factors control granulostasis; (2) nuclear transport factors regulate RNA homeostasis in the cytoplasm. SPECIFIC AIMS. We will test our hypotheses in cell-free, cellular and organismal model systems. In particular, we will: (1) Define the role of nuclear transport factors for stress granule assembly, dynamics, dissolution and fibrillization; (2) Characterize cytoplasmic RNA damage granules. IMPACT. Based on results we recently obtained, our research program takes a novel and exciting direction that explores the unexpected and ill-defined functions of nuclear transport factors as they relate to cytoplasmic RNA granules. We will focus on the underlying biological mechanisms that are largely unknown. Thus, our research will identify the contributions of nuclear transport factors to a complex quality control system that regulates cellular homeostasis. These important biological processes are relevant to all eukaryotic cells. The insights generated by us will help define basic principles that promote cellular homeostasis. We will achieve this through rigorous and multidisciplinary research that uses state-of-the-art methods and instrumentation.