Selective sorting of microRNAs into exosomes by phase-separated YBX1 condensates

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Abstract

Exosomes may mediate cell-to-cell communication by transporting various proteins and nucleic acids to neighboring cells. Some protein and RNA cargoes are significantly enriched in exosomes. How cells efficiently and selectively sort them into exosomes remains incompletely explored. Previously we reported that YBX1 is required in sorting of miR-223 into exosomes. Here we show that YBX1 undergoes liquid-liquid phase separation (LLPS) in vitro and in cells. YBX1 condensates selectively recruit miR-223 in vitro and into exosomes secreted by cultured cells. Point mutations that inhibit YBX1 phase separation impair the incorporation of YBX1 protein into biomolecular condensates formed in cells, and perturb miR-233 sorting into exosomes. We propose that phase separation-mediated local enrichment of cytosolic RNA binding proteins and their cognate RNAs enables their targeting and packaging by vesicles that bud into multivesicular bodies. This provides a possible mechanism for efficient and selective engulfment of cytosolic proteins and RNAs into intraluminal vesicles which are then secreted as exosomes from cells.

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All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figure 3-figure supplement 2D, Figure 4C, Figure 4D, Figure 4E, Figure 4F, Figure 4I, Figure 4K, Figure 5C, Figure 7G, Figure 7H, Figure 7I, and Figure 7-figure supplement 3B; Numerical data that are represented as graphs for Figure 5 and Figure 6; Table 1, Table 2 and Table3 as source data corresponding to Figure 7F and Figure 7J.

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Xiao-Man Liu

Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0001-9968-3988
Liang Ma

Howard Hughes Medical Institute, University of California, Berkeley, BERKELEY, United States

Competing interests
No competing interests declared.
Randy Schekman

Howard Hughes Medical Institute, University of California, Berkeley, BERKELEY, United States

For correspondence
schekman@berkeley.edu

Competing interests
Randy Schekman, Reviewing editor, eLife and Founding Editor-in-Chief, eLife..

"This ORCID iD identifies the author of this article:" 0000-0001-8615-6409

Funding

Howard Hughes Medical Institute (Investigator)

Randy Schekman

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

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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.