Role of HSP70 in the regulation of miRNA biogenesis in heat stressed cells

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Environmental stress or disease can result in protein damage, which is toxic to cells and can lead to inappropriate cell death. Cells respond to stressful stimuli by activating an evolutionarily conserved ‘heat shock response’ that results in the increased production of heat shock proteins. These proteins function as molecular chaperones and are part of a defense mechanism that acts to limit the extent of protein damage and thereby allow cells and organisms to survive proteotoxic stresses. Stress-induced cell death occurs through a regulated process of cell elimination known as apoptosis, which is controlled by pro- and anti-apoptotic members of the BCL2 family. A fundamental question in cell biology is how cells regulate the decision to initiate the process of apoptotic cell destruction. The overarching focus of my research program has been to examine the role of heat-shock proteins in this decision-making process. Our work led to the original demonstration that the major heat-shock protein HSP70 prevents stress-induced apoptosis. The long-term goals of my research program are to determine how hyperthermia triggers apoptosis and how HSP70 prevents this from occurring. We have established a role for the pro-apoptotic BCL2 family protein NOXA in heat-induced apoptosis. We demonstrated that HSP70 prevents the heat-induced accumulation of NOXA. We also showed that this occurs through modulation of a microRNA (miR-23a) that regulates NOXA protein synthesis. Experiments in this proposal will examine the mechanisms controlling miRNA biogenesis in heat stressed cells and how they are regulated by HSP70. We plan to identify the transcription factors regulating pri-miR-23a expression and examine how their activity is controlled by the interplay between hyperthermia and HSP70. Recent studies have shown that microRNAs can be released by cells and delivered to recipient cells within exosomes. We plan to examine the effect of hyperthermia and HSP70 overexpression on exosomal miRNA export. The results of these studies will provide insight into the effects of hyperthermia on microRNA biogenesis and the role of HSP70 in protecting this vital process. They will establish the foundation for an as-yet-unexplored area of cell biology that is likely to have a significant impact on a fundamental area of research in the natural sciences and could potentially lead to studies that would apply this knowledge to disease states. For example, microRNAs play essential roles in regulating nearly all aspects of cell biology and their deregulation contributes to a number of human diseases including cancer. HSP70 overexpression and apoptosis suppression are defining features of cancer cells whereas a decline in the ability to produce HSP70 occurs during aging. However the effects of proteotoxic stress on microRNA biogenesis and its relationship to disease are poorly understood as is the role of HSP70.