Abstract

Extracellular Vesicles Go Nuclear

Aurelio Lorico, Professor of Pathology, Touro University Nevada School of Medicine

Molecular mechanisms regulating EV biogenesis, their release, and subsequent uptake by target cells have emerged during the last two decades. How their cargo molecules are selectively delivered to their intracellular sites of action, including the intra-nuclear compartment, is still obscure. This issue is particularly important given that the biogenesis and functionality of EVs are dysregulated under pathological conditions. Recently, we described a novel sub-nuclear compartment which is created by the entry of small GTPase Rab7-containing late endosomes in the nucleoplasmic reticulum. The latter is shaped by superficial and deep nuclear envelope invaginations (NEI) penetrating into the nucleoplasm. Given that late endosomes in NEI has often an elongated appearance and resembles a sword in its scabbard, we proposed to name this dual-structure “spathasome” from Greek/Latin words “spathi/spatha” for sword. This structure appears to act as an intermediate compartment for the delivery of the content of endocytosed EVs (e.g., CD9/CD133 protein complexes and RNA molecules) to the nucleoplasm of their host cell. The NEI-associated late endosomes and nuclear localization of EV-derived proteins were observed in cancer cells and mesenchymal stromal cells in cultures and in breast cancer patient biopsies. A molecular complex, investigated by indirect immunofluorescence, fluorescence resonance energy transfer, immunoisolation techniques and RNA interference, was found to be responsible for the entry of EV cargo into the nucleoplasmic reticulum.