Mechanisms of microRNA export in mammalian cells: From random release to selective secretion

Extracellular vesicles (EVs) are essential carriers of information between cells and tissues in multicellular (metazoan) organisms. MicroRNAs (miRNAs), key components of extracellular vesicles along with other non-RNA cargo, play a crucial role in regulating gene expression in both donor and recipient cells. Several questions about the basis and mechanisms of miRNA sorting into EVs have been raised, some of which have recently been addressed in reports on RNA-binding proteins and miRNA motifs that enable selective miRNA export. Recent studies indicate that both active and passive mechanisms of miRNA export occur in mammalian cells, underscoring that miRNA export is a selective and context-dependent process. This flexibility in the export process allows mammalian cells to respond quickly to changing environments. This review explores the mechanisms of miRNA export, the roles of RNA-binding proteins in this process, highlighting how these proteins enable the selective secretion of miRNAs across different mammalian cell types. EV-mediated export facilitates a targeted exchange mechanism for epigenetic signals like miRNAs, evolving from what initially appeared to be a random release process. Additionally, we have discussed the key unresolved questions regarding miRNA export and its evolution as a major mechanism of intercellular communication in metazoans.