While microRNAs (miRNAs) are known to shuttle from cell to cell via exosomes, exactly how miRNAs are captured by the cell’s export machinery is poorly understood. Recently, however, miRNAs have divulged at least one detail about their comings and goings. miRNAs contain sequence motifs, called EXOmotifs, that control their localization in exosomes.
This discovery about the loading of miRNAs into exosomes, or nanoscale vesicles, was made by a team of researchers directed by Professor Francisco Sánchez-Madrid, Ph.D., who is affiliated with the Universidad Autónoma de Madrid and the CNIC (Centro Nacional de Investigaciones Cardiovasculares). The team described their work in the December 20 edition of Nature Communications, in an article entitled “Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs.”
In this article, the authors identified short sequence motifs overrepresented in miRNAs that are commonly enriched in exosomes. “These motifs control the loading of these miRNAs into exosomes,” they wrote, “and their directed mutagenesis enables the modulation of miRNA cargo in these vesicles.” According to the authors, these motifs allow exosomal miRNAs to be specifically recognized (and bound) by a transport protein, heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1). The authors also noted that hnRNPA2B1 in exosomes is sumoylated, and sumoylation controls the binding of hnRNPA2B1 to miRNAs.
hnRNPA2B1 plays various roles. It is known to bind to a 21-nucleotide RNA trafficking sequence that occurs in the 3′ untranslated region (UTR) of the myelin basic protein mRNA. hnRNPA2B1 is also implicated in the transport of the genomic RNA of viruses such as HIV to sites of exit to the cell exterior. This establishes a parallel between the secretion of vesicles loaded with RNA and the production of viruses that parasitize the cellular machinery to extend infection.
Speculating on how hnRNPA2B1 is able to transport RNA to exosomes, the authors commented that the transport protein probably depends on its ability to interact with cytoskeletal components: “Indeed, there is evidence that in neurons hnRNPA2B1 partly regulates motor activity through indirect contacts with microtubules, and monomeric or short oligomeric actin has been shown to associate with a subset of hnRNPs, including hnRNPA2B1.”
In summing up the implications of their work, the authors concluded that their findings may lead to “tools for the packaging of selected regulatory RNAs into exosomes and their use in biomedical applications.” Custom packages of miRNA would have enormous potential as vehicles for gene therapy, vaccines, and antitumor treatments.