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Distinct mechanisms of microRNA sorting into cancer cell-derived extracellular vesicle subtypes

Temoche-Diaz, Morayma M, Shurtleff, Matthew J, Nottingham, Ryan M, Yao, Jun, Fadadu, Raj P, Lambowitz, Alan M, Schekman, Randy·2019·eLife

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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.

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Metadata

Authors
Temoche-Diaz, M. M., Shurtleff, M. J., Nottingham, R. M., Yao, J., Fadadu, R. P., Lambowitz, A. M., & Schekman, R.
Affiliations
  • Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, United States
  • Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, University of Texas, Austin, United States
  • Department of Molecular and Cellular Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States
Venue
eLife
Published
2019-08-22
Volume
8
ISSN
2050-084X
Cited by
227
References
12
Language
en
Funders
  • Howard Hughes Medical Institute
  • National Institutes of Health (R01 GM37949)

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