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Proc Natl Acad Sci U S A. 2017 Nov 14;114(46):E9873-E9882. doi: 10.1073/pnas.1706365114. Epub 2017 Oct 24.

Intercellular mRNA trafficking via membrane nanotube-like extensions in mammalian cells.

Author information

1
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.
2
Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY 10461.
3
Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104.
4
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel; jeffrey.gerst@weizmann.ac.il robert.singer@einstein.yu.edu.
5
Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY 10461; jeffrey.gerst@weizmann.ac.il robert.singer@einstein.yu.edu.
6
Janelia Research Campus of the Howard Hughes Medical Institute, Ashburn, VA 20147.

Abstract

RNAs have been shown to undergo transfer between mammalian cells, although the mechanism behind this phenomenon and its overall importance to cell physiology is not well understood. Numerous publications have suggested that RNAs (microRNAs and incomplete mRNAs) undergo transfer via extracellular vesicles (e.g., exosomes). However, in contrast to a diffusion-based transfer mechanism, we find that full-length mRNAs undergo direct cell-cell transfer via cytoplasmic extensions characteristic of membrane nanotubes (mNTs), which connect donor and acceptor cells. By employing a simple coculture experimental model and using single-molecule imaging, we provide quantitative data showing that mRNAs are transferred between cells in contact. Examples of mRNAs that undergo transfer include those encoding GFP, mouse β-actin, and human Cyclin D1, BRCA1, MT2A, and HER2. We show that intercellular mRNA transfer occurs in all coculture models tested (e.g., between primary cells, immortalized cells, and in cocultures of immortalized human and murine cells). Rapid mRNA transfer is dependent upon actin but is independent of de novo protein synthesis and is modulated by stress conditions and gene-expression levels. Hence, this work supports the hypothesis that full-length mRNAs undergo transfer between cells through a refined structural connection. Importantly, unlike the transfer of miRNA or RNA fragments, this process of communication transfers genetic information that could potentially alter the acceptor cell proteome. This phenomenon may prove important for the proper development and functioning of tissues as well as for host-parasite or symbiotic interactions.

KEYWORDS:

MS2; membrane nanotubes; smFISH; β-actin mRNA

PMID:
29078295
PMCID:
PMC5699038
DOI:
10.1073/pnas.1706365114
[Indexed for MEDLINE]
Free PMC Article

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