Extracellular vesicle-dependent RNA signaling in metabolism

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In conventional metabolic signaling, secreted protein hormones such as insulin and glucagon elicit metabolic responses in target cells by binding to surface receptors. Recently, a new paradigm of metabolic signaling has emerged, where RNAs act as signaling molecules. For effective intercellular signaling, RNAs (e.g., microRNAs) must be transferred from donor to recipient cells via extracellular vesicles (EVs)—membranous particles released by nearly all cell types.

EVs are released from donor cells either through secretion of intraluminal vesicles enclosed in multivesicular bodies/endosomes (exosomes) or by budding from the plasma membrane (microvesicles). When EVs fuse with the surface or endosome of recipient cells, the encapsulated RNAs are delivered into the recipient cell's cytosol, where they regulate gene expression.

Previous studies have primarily provided evidence of EV-dependent RNA signaling through the deletion of RNAs from EVs and the inhibition of EV release from donor cells. However, these studies have not demonstrated the critical role of EV fusion with recipient cells, leaving open the possibility that metabolic responses might be triggered by non-RNA molecules co-purified with EVs or present on the EV surface.

In this pilot project, we will conduct biochemical and genetic experiments to identify proteins crucial for EV-mediated delivery of adipose microRNAs into liver cells, with a focus on noncanonical proteins that have been overlooked in previous research. If such proteins are identified, we will develop genetic strategies to test whether EV fusion-mediated RNA delivery is necessary for metabolic signaling between adipocytes and liver cells.

These pilot studies are expected to provide insights into the pathogenesis of metabolic diseases associated with RNA signaling and facilitate the development of novel therapeutics.