Exosome Uptake Depends on ERK1/2-Heat Shock Protein 27 Signaling and Lipid Raft-mediated Endocytosis Negatively Regulated by Caveolin-1

By Katrin J. Svensson, H. Christianson, Anders Wittrup, E. Bourseau-Guilmain, E. Lindqvist, L. Svensson, M. Mörgelin, Mattias Belting. Journal of Biological Chemistry, 2013

651 citations recorded by the source corpus.

Background: Exosome vesicles can transfer molecular information previously shown to stimulate tumor development; however, the mechanism of exosome uptake is unknown. Results: Mammalian cells internalize exosomes through lipid raft-mediated endocytosis negatively regulated by caveolin-1. Conclusion: Our findings provide novel insights into cellular uptake of exosomes. Significance: Our data provide potential strategies for how the exosome uptake pathway may be targeted. The role of exosomes in cancer can be inferred from the observation that they transfer tumor cell derived genetic material and signaling proteins, resulting in e.g. increased tumor angiogenesis and metastasis. However, the membrane transport mechanisms and the signaling events involved in the uptake of these virus-like particles remain ill-defined. We now report that internalization of exosomes derived from glioblastoma (GBM) cells involves nonclassical, lipid raft-dependent endocytosis. Importantly, we show that the lipid raft-associated protein caveolin-1 (CAV1), in analogy with its previously described role in virus uptake, negatively regulates the uptake of exosomes. We find that exosomes induce the phosphorylation of several downstream targets known to associate with lipid rafts as signaling and sorting platforms, such as extracellular signal-regulated kinase-1/2 (ERK1/2) and heat shock protein 27 (HSP27). Interestingly, exosome uptake appears dependent on unperturbed ERK1/2-HSP27 signaling, and ERK1/2 phosphorylation is under negative influence by CAV1 during internalization of exosomes. These findings significantly advance our general understanding of exosome-mediated uptake and offer potential strategies for how this pathway may be targeted through modulation of CAV1 expression and ERK1/2 signaling.

Subfields: Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/3f58b124db295e1e65d911819efecd73d4364962

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Citations in the corpus

Review of the Isolation, Characterization, Biological Function, and Multifarious Therapeutic Approaches of Exosomes (2019, background): “Glioblastoma cell-derived exosomes were internalized through lipid raft-mediated endocytosis negatively regulated by caveolin-1 [224].”
Advances in therapeutic applications of extracellular vesicles (2019, background): “EVs have been suggested to be internalized into target cells by various uptake mechanisms including membrane fusion (171) and different endocytic pathways including phagocytosis (172), receptor-mediated endocytosis (173), lipid raft–mediated endocytosis (174), clathrin-mediated endocytosis (175), ca”
Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. (2014, background): “…phagocytosis but also clathrin-dependent endocytosis in neurons (Fruhbeis et al. 2013); clathrin-independent but cholesterol- and lipid raft–dependent endocytosis in endothelial and some tumor cells (Svensson et al. 2013); or caveolae-dependent endocytosis in epithelial cells (Nanbo et al. 2013).”
Routes and mechanisms of extracellular vesicle uptake (2014, background): “EV uptake was prevented following pre-treatment of recipient cells with the cholesterol reducing agents MbCD (26,27,41,47), filipin (22,26,34) and simvastatin (26).”
Introduction to Extracellular Vesicles: Biogenesis, RNA Cargo Selection, Content, Release, and Uptake (2016, neutral): “…cells, caveolin-mediated endocytosis in epithelial cells, and cholesterol-and lipid raft-dependent endocytosis in tumor cells (Morelli et al. 2004; Barrès et al. 2010; Feng et al. 2010; Fitzner et al. 2011; Montecalvo et al. 2012; Frühbeis et al. 2013; Nanbo et al. 2013; Svensson et al. 2013).”
Mesenchymal Stem Cell Secretome: Toward Cell-Free Therapeutic Strategies in Regenerative Medicine (2017, background): “Exosomes may subsequently be internalized by other cells principally by phagocytosis, fusion with the cell membrane and receptor–ligand interaction, allowing the release of their contents into the cytoplasm [168,169].”