Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs

By Carolina Villarroya-Beltri, Cristina Gutiérrez-Vázquez, Fátima Sánchez-Cabo, Daniel Perez-Hernandez, Jesús Vázquez, N. Martín-Cófreces, D. J. Martínez-Herrera, Alberto Domingo Pascual-Montano, M. Mittelbrunn, F. Sánchez‐Madrid. Nature Communications, 2013

1,837 citations recorded by the source corpus.

Exosomes are released by most cells to the extracellular environment and are involved in cell-to-cell communication. Exosomes contain specific repertoires of mRNAs, microRNAs (miRNAs) and other non-coding RNAs that can be functionally transferred to recipient cells. However, the mechanisms that control the specific loading of RNA species into exosomes remain unknown. Here we describe sequence motifs present in miRNAs that control their localization into exosomes. The protein heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) specifically binds exosomal miRNAs through the recognition of these motifs and controls their loading into exosomes. Moreover, hnRNPA2B1 in exosomes is sumoylated, and sumoylation controls the binding of hnRNPA2B1 to miRNAs. The loading of miRNAs into exosomes can be modulated by mutagenesis of the identified motifs or changes in hnRNPA2B1 expression levels. These findings identify hnRNPA2B1 as a key player in miRNA sorting into exosomes and provide potential tools for the packaging of selected regulatory RNAs into exosomes and their use in biomedical applications. Cells secrete micro-RNAs by packaging them into exosomes; however, the mechanisms by which this packaging occurs are unclear. Here, the authors identify a sequence motif that confers exosomal targeting to micro-RNAs and identify a ribonucleoprotein complex that plays a role in this process.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/989b9bd66fecdf62494a1aef6c721dea257b169b

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In Cancer Research

1. Marina Colombo
2. C. Théry
3. G. Raposo
4. P. Vader
5. Yan Luo
6. Ben Wang
7. Chuanjiang He
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In Molecular Biology

1. C. Théry
2. G. Raposo
3. Marina Colombo
4. María Yáñez-Mó
5. P. Vader
6. Zoraida Andreu
7. Jan Lötvall
8. Yan Luo

Citations in the corpus

• Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. (2014, background): “A recent study identified a specific sequence within miRNA, which binds to a sumoylated ribonucleoprotein to induce their targeting to EVs in T cells (Villarroya-Beltri et al. 2013).”
• Mechanisms of mesenchymal stem/stromal cell function (2016, background): “For example, MSCs isolated from various tissues differ in terms of exosome content [184, 185] and MSCs from bone marrow with multiple myeloma were reported to differ in miRNA content relative to MSCs from control bone marrow [183].”
• Tetraspanins in Extracellular Vesicle Formation and Function (2014, background): “Several miRNAs present specific EXOmotifs (GGAG) that are able to bind to heterogeneous ribonucleoprotein A2B1 (hnRNPA2B1), which is responsible for the trafficking of these miRNAs into EVs (105).”
• Applying extracellular vesicles based therapeutics in clinical trials – an ISEV position paper (2015, positive): “The feasibility of this method, however, likely varies depending on the siRNA or miRNA species, as cells seem to have selective sorting mechanisms for the incorporation of small RNAs into EVs (235,236).”
• Exosome Theranostics: Biology and Translational Medicine (2018, background): “Similarly, there is a tetranucleotide sequence that can induce the packaging of microRNA into exosomes and is recognized by heterogeneous nuclear ribonucleoproteins [84].”
• In Vivo Imaging Reveals Extracellular Vesicle-Mediated Phenocopying of Metastatic Behavior (2015, background): “The enrichment of these biomolecules can be explained by specific loading (e.g., Villarroya-Beltri et al., 2013) or by non-specific loading of biomolecules located at peripheral cell region in EVs that are released at the edge of cells.”
• Exosome and Exosomal MicroRNA: Trafficking, Sorting, and Function (2015, background): “Villarroya-Beltri et al. discovered that sumoylated hnRNPA2B1 could recognize the GGAG motif in the 3 0 portion of miRNA sequences and cause specific miRNAs to be packed into exosomes [59].”