MicroRNA sequence codes for small extracellular vesicle release and cellular retention

Ruben Garcia-Martin, Guoxiao Wang, Bruna B. Brandão, Tamires M. Zanotto, Samah Shah, Sandip Kumar Patel, Birgit Schilling and C. Ronald Kahn ()
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Ruben Garcia-Martin: Harvard Medical School
Guoxiao Wang: Harvard Medical School
Bruna B. Brandão: Harvard Medical School
Tamires M. Zanotto: Harvard Medical School
Samah Shah: The Buck Institute for Research on Aging
Sandip Kumar Patel: The Buck Institute for Research on Aging
Birgit Schilling: The Buck Institute for Research on Aging
C. Ronald Kahn: Harvard Medical School

Nature, 2022, vol. 601, issue 7893, 446-451

Abstract: Abstract Exosomes and other small extracellular vesicles (sEVs) provide a unique mode of cell-to-cell communication in which microRNAs (miRNAs) produced and released from one cell are taken up by cells at a distance where they can enact changes in gene expression1–3. However, the mechanism by which miRNAs are sorted into exosomes/sEVs or retained in cells remains largely unknown. Here we demonstrate that miRNAs possess sorting sequences that determine their secretion in sEVs (EXOmotifs) or cellular retention (CELLmotifs) and that different cell types, including white and brown adipocytes, endothelium, liver and muscle, make preferential use of specific sorting sequences, thus defining the sEV miRNA profile of that cell type. Insertion or deletion of these CELLmotifs or EXOmotifs in a miRNA increases or decreases retention in the cell of production or secretion into exosomes/sEVs. Two RNA-binding proteins, Alyref and Fus, are involved in the export of miRNAs carrying one of the strongest EXOmotifs, CGGGAG. Increased miRNA delivery mediated by EXOmotifs leads to enhanced inhibition of target genes in distant cells. Thus, this miRNA code not only provides important insights that link circulating exosomal miRNAs to tissues of origin, but also provides an approach for improved targeting in RNA-mediated therapies.

Date: 2022
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DOI: 10.1038/s41586-021-04234-3

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