Two RNA-binding proteins mediate the sorting of miR223 from mitochondria into exosomes
- Howard Hughes Medical Institute, University of California, Berkeley, United States
Abstract
Fusion of multivesicular bodies (MVBs) with the plasma membrane results in the secretion of intraluminal vesicles (ILVs), or exosomes. The sorting of one exosomal cargo RNA, miR223, is facilitated by the RNA-binding protein, YBX1 (Shurtleff et al., 2016). We found that miR223 specifically binds a 'cold shock' domain (CSD) of YBX1 through a 5' proximal sequence motif UCAGU that may represent a binding site or structural feature required for sorting. Prior to sorting into exosomes, most of the cytoplasmic miR223 resides in mitochondria. An RNA-binding protein localized to the mitochondrial matrix, YBAP1, appears to serve as a negative regulator of miR223 enrichment into exosomes. miR223 levels decreased in the mitochondria and increased in exosomes after loss of YBAP1. We observed YBX1 shuttle between mitochondria and endosomes in live cells. YBX1 also partitions into P body granules in the cytoplasm (Liu et al., 2021). We propose a model in which miR223 and likely other miRNAs are stored in mitochondria and are then mobilized by YBX1 to cytoplasmic phase condensate granules for capture into invaginations in the endosome that give rise to exosomes.
Data availability
All data generated or analyzed in this study are included in the manuscript and supporting files. Source data files have been provided for Figure 1b, Figure 1c, Figure 1f, Figure 1g, Figure 1-figure supplement 2a-c, Figure 2b, Figure 2g, Figure 2-figure supplement 1a-f, Figure 3a, Figure 3c, Figure 3e, Figure 3h, Figure 3 supplement 1b-c, Figure 4a, Figure 4b, Figure 4e, Figure 4f, Figure 4h, Figure 4i, Figure 4-figure supplement 1a-b, Figure 4-figure supplement 2a, Figure 5b.
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Funding
Howard Hughes Medical Institute
- Randy Schekman
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2023, Ma et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Two RNA-binding proteins mediate the sorting of miR223 from mitochondria into exosomes
eLife 12:e85878.
https://doi.org/10.7554/eLife.85878
Further reading
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