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New insights on cell-to-cell communication—mRNA “zip codes”

Researchers have identified short genetic sequences on microRNAs (miRNAs) that help determine which miRNAs are retained by the cell that produced them and which are released to affect other cells. This knowledge provides important new insights into cell-to-cell communication and could inform the development of therapies for diseases associated with miRNA dysfunction. miRNAs are very short RNA molecules involved in regulating gene activity and play a role in both health and disease; miRNA dysfunction has been linked to type 2 diabetes, obesity, and other diseases. miRNAs may be retained by their parent cell or released in exosomes—small cellular delivery packages that transfer miRNAs and proteins from one cell to another. However, the mechanisms by which cells determine which miRNAs go where are not understood.

To address this gap in knowledge, scientists examined miRNAs in exosomes secreted by different types of mouse cells grown in the laboratory, including fat cells (adipocytes), liver cells, and other cells, finding that each cell type secreted different miRNAs in their exosomes. Additionally, some miRNAs were more likely to be found in exosomes, while others were mostly retained by the cell that produced them, suggesting a mechanism of miRNA sorting. To understand how the sorting occurred, the scientists studied whether specific genetic sequences in miRNAs determined whether they were packaged into exosomes or retained by cells—was there a “zip code” telling the cell where miRNAs should go? Indeed, experiments identified several short sequence motifs associated with miRNAs either being released in exosomes (called EXOmotifs) or retained by cells (called CELLmotifs); interestingly, each of the cell types studied used different sequence motifs, suggesting that there is no one universal exosome “addressing” system. The scientists next confirmed the importance of these motifs by showing that genetically modifying an miRNA’s sequence motif “zip code” changed its location. For example, adding an EXOmotif to one of the cellular miRNAs promoted its release into exosomes. This redirection of miRNAs led to changes in gene activity in the recipient cells, suggesting that altering these sequence motifs to change the location of miRNAs could be used to affect downstream cellular activity.

These results provide new understanding about how cells sort miRNAs and communicate with one another. Further understanding of the mechanisms underlying miRNA sorting could facilitate new approaches for miRNA-based therapies for a variety of diseases.

Garcia-Martin R, Wang G, Brandão BB,…Kahn CR. MicroRNA sequence codes for small extracellular vesicle release and cellular retention. Nature 601: 446-451, 2022.

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