Abstract
Extracellular membrane vesicles (EVs) are emerging as new vehicles in intercellular communication, but how the biological information contained in EVs is shared between cells remains elusive. Several mechanisms have been described to explain their release from donor cells and the initial step of their uptake by recipient cells, which triggers a cellular response. Yet, the intracellular routes and subcellular fate of EV content upon internalization remain poorly characterized. This is particularly true for EV-associated proteins and nucleic acids that shuttle to the nucleus of host cells. In this review, we will describe and discuss the release of EVs from donor cells, their uptake by recipient cells, and the fate of their cargoes, focusing on a novel intracellular route wherein small GTPase Rab7+ late endosomes containing endocytosed EVs enter into nuclear envelope invaginations and deliver their cargo components to the nucleoplasm of recipient cells. A tripartite protein complex composed of (VAMP)-associated protein A (VAP-A), oxysterol-binding protein (OSBP)-related protein-3 (ORP3), and Rab7 is essential for the transfer of EV-derived components to the nuclear compartment by orchestrating the particular localization of late endosomes in the nucleoplasmic reticulum.
Highlights
Intercellular communication is a fundamental feature for the development and maintenance of multicellular organisms
In search for the mechanism regulating the transfer of biomaterials from extracellular membrane vesicles (EVs) to their molecular targets in recipient cells, notably in the nuclear compartment, we observed that a fraction of EV-associated proteins, upon EV endocytosis, ends in type II nuclear envelope invagination (NEI), suggesting that the endocytic system can be involved in nuclear transfer [5,160]
Since solely a minute fraction of EV-loaded late endosomes ended up in NEI in a steady-state condition, it remains to be determined whether they are derived from StAR-related lipid transfer domain containing 3 (STARD3)+ “early” or oxysterol-binding protein (OSBP)-related protein 1L (ORP1L)+ “late” late endosomes, as defined by the fluid-phase cargo transport [162]
Summary
Intercellular communication is a fundamental feature for the development and maintenance of multicellular organisms. Diverse molecular mechanisms for the exchange of biological information between cells have been documented. The secretion of soluble proteins and their interaction with membrane receptors located on the target cells or contact-dependent signaling are good examples. To better understand the mechanism that triggers molecular crosstalk between cells, we came to the fascinating and poorly explored world of extracellular membrane vesicles (EVs) [1,2,3,4]. We will review here the mechanisms underlying the release of different types of EVs from donor cells into the. Cells 2020, 9, 1931 extracellular medium, their uptake by recipient cells, and the fate of their cargoes with a focus on a new intracellular pathway that led to their transfer into the nuclear compartment [5,6]
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