Role of long non-coding RNAs in exosome biogenesis

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SUMMARY Exosomes are nano-sized vesicles secreted into the extracellular milieu by all cells in physiological and pathological states. Exosomes can effectively mediate cell-cell communications, deliver macromolecules such as proteins and nucleic acids to cells, and induce functional changes in recipient cells. Recent studies have implicated that exosomes participate in a broad range of pathophysiological processes, including immune regulation, organogenesis, and carcinogenesis. Despite great interest in exosomes for both diagnostics and therapeutics applications, the basic understanding of the regulation of exosome secretion is not well established. Long noncoding RNAs (lncRNAs), defined as RNAs longer than 200nt without functional protein-coding capacity, are emerging as regulators of gene expression and cellular functions. Our preliminary data has shown that lncRNAs play regulatory roles in exosome biogenesis in both physiologic and cellular stress conditions, such as hypoxia and oxidative stress. How the biogenesis, intracellular trafficking, and cargo soring of the exosomes are regulated by lncRNAs is largely unknown. This project will investigate the role of cytoplasmic and nuclear lncRNAs in exosome biogenesis and identify how they function in the docking, cargo sorting, and fusion of late endosomes or multivesicular bodies to the plasma membrane. The role of lncRNA in the regulation of signaling pathways and genes that regulate different aspects of exosome biogenesis and exosome cargo selection will also be characterized. We will investigate how cellular stress pathways, such as the HIF1-alpha and MAPK pathways, through lncRNA or independent of the lncRNAs, influence exosome biogenesis and cargo selection. Research accomplishments from this project will deepen our understanding of the basic biology of regulation of exosome biogenesis and open new avenues for the therapeutic use of exosomes and lncRNAs in the treatment of various diseases. Exosomes play a vital role in many biological processes, including adaptive immune function, cancer metastasis, the development and differentiation of stem cells, tissue regeneration, and viral replication. They also exhibit profiles specific to the cell of origin and therefore represent novel biomarkers that show promise for improving disease diagnosis. Their central role in cell-to-cell communication presents opportunities for the development of improved therapeutics. Therefore, it is essential to understand the role of lncRNAs in regulating exosome production and release in order to realize these diagnostic and therapeutic opportunities.