Neuropilin-1 is a receptor for extracellular miRNA and AGO2/miRNA complexes and mediates the internalization of miRNAs that modulate cell function
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Gerald J. Prud’homme1,2,3, Yelena Glinka1, Zsuzsanna Lichner1, George M. Yousef1,2,3
1Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Toronto, ON M5B 1W8, Canada
2Department of Laboratory Medicine, St. Michael’s Hospital, Toronto, ON M5B 1W8, Canada
3Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5G 1L5, Canada
Gerald J. Prud’homme, email: [email protected]
Keywords: miRNA, endocytosis, endothelial cells, neuropilin, renal cell carcinoma
Received: April 15, 2016 Accepted: July 19, 2016 Published: July 29, 2016
Extracellular miRNAs are increasingly studied as markers for specific diseases. They are released in biological fluids in a remarkably stable form, and may play a role in intercellular communication. They are thought to be protected against degradation by either encapsulation within microparticles, or by binding to proteins (mostly AGO2). The particulate forms may be internalized by endocytosis or membrane fusion, but the protein-bound forms require a receptor mechanism for their uptake. A major question is whether there are natural cell-membrane receptors that capture and internalize protein-bound functional miRNAs. We examined neuropilin-1 (NRP1), in view of its properties as a receptor for many ligands, including growth factors such as vascular endothelial growth factor (VEGF), and efficiency at mediating ligand internalization. It is expressed by endothelial cells, many other normal cell types, and cancer cells. Here, we report that NRP1 binds miRNAs with high affinity, and promotes their entry into the cell. Furthermore, the internalized miRNAs remain functional, as they specifically regulate proliferation and migration of cancer cells, as well as tube formation by human endothelial cells. Anti-NRP1 antibodies or NRP1 siRNA knockdown block miRNA effects, further confirming NRP1-mediated uptake. VEGF does not compete with miRNAs for binding to NRP1. In addition, NRP1 binds extracellular AGO2 (carrying miRNA or not), and internalizes AGO2/miRNA complexes. Because miRNA bound to AGO2 appears to the most abundant form in body fluids, this may have important physiological and pathological effects.
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