Two RNA-binding proteins mediate the sorting of miR223 from mitochondria into exosomes

  1. Liang Ma
  2. Jasleen Singh
  3. Randy Schekman  Is a corresponding author
  1. 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.

Article and author information

Author details

  1. Liang Ma

    Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  2. Jasleen Singh

    Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  3. Randy Schekman

    Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States
    For correspondence
    schekman@berkeley.edu
    Competing interests
    Randy Schekman, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8615-6409

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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  1. Liang Ma
  2. Jasleen Singh
  3. Randy Schekman
(2023)
Two RNA-binding proteins mediate the sorting of miR223 from mitochondria into exosomes
eLife 12:e85878.
https://doi.org/10.7554/eLife.85878

Share this article

https://doi.org/10.7554/eLife.85878

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