1. Biochemistry and Chemical Biology
  2. Cancer Biology
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Distinct mechanisms of microRNA sorting into cancer cell-derived extracellular vesicle subtypes

  1. Morayma M Temoche-Diaz
  2. Matthew J Shurtleff
  3. Ryan M Nottingham
  4. Jun Yao
  5. Raj P Fadadu
  6. Alan M Lambowitz
  7. Randy Schekman  Is a corresponding author
  1. University of California, Berkeley, United States
  2. University of California, San Francisco, United States
  3. University of Texas at Austin, United States
  4. Howard Hughes Medical Institute, University of California, Berkeley, United States
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Cite this article as: eLife 2019;8:e47544 doi: 10.7554/eLife.47544

Abstract

Extracellular vesicles (EVs) encompass a variety of vesicles secreted into the extracellular space. EVs have been implicated in promoting tumor metastasis, but the molecular composition of tumor-derived EV sub-types and the mechanisms by which molecules are sorted into EVs remain mostly unknown. We report the separation of two small EV sub-populations from a metastatic breast cancer cell line, with biochemical features consistent with different sub-cellular origins. These EV sub-types use different mechanisms of miRNA sorting (selective and non-selective), suggesting that sorting occurs via fundamentally distinct processes, possibly dependent on EV origin. Using biochemical and genetic tools, we identified the Lupus La protein as mediating sorting of selectively packaged miRNAs. We found that two motifs embedded in miR-122 are responsible for high-affinity binding to Lupus La and sorting into vesicles formed in a cell-free reaction. Thus, tumor cells can simultaneously deploy multiple EV species using distinct sorting mechanisms that may enable diverse functions in normal and cancer biology.

Article and author information

Author details

  1. Morayma M Temoche-Diaz

    Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1119-1749
  2. Matthew J Shurtleff

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9846-3051
  3. Ryan M Nottingham

    Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6937-5394
  4. Jun Yao

    Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, United States
    Competing interests
    No competing interests declared.
  5. Raj P Fadadu

    Department of Molecular and Cellular Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  6. Alan M Lambowitz

    Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, United States
    Competing interests
    Alan M Lambowitz, Thermostable group II intron reverse transcriptase (TGIRT) enzymes and methods for their use are the subject of patents and patent applications that have been licensed by the University of Texas and East Tennessee State University to InGex, LLC. A.M.L., some former and present members of the A.M.L. laboratory, and the University of Texas are minority equity holders in InGex, LLC and receive royalty payments from the sale of TGIRT enzymes and kits and from the sublicensing of intellectual property to other companies..
  7. Randy Schekman

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

Funding

Howard Hughes Medical Institute

  • Randy Schekman

National Institutes of Health (R01 GM37949)

  • Alan M Lambowitz

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Suzanne R Pfeffer, Stanford University School of Medicine, United States

Publication history

  1. Received: April 9, 2019
  2. Accepted: August 21, 2019
  3. Accepted Manuscript published: August 22, 2019 (version 1)
  4. Version of Record published: September 5, 2019 (version 2)
  5. Version of Record updated: October 14, 2019 (version 3)

Copyright

© 2019, Temoche-Diaz 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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