The ins and outs of microvesicles

Abstract

Microvesicles are a heterogeneous group of membrane-enclosed vesicles that are released from cells into the extracellular space by the outward budding and pinching of the plasma membrane. These vesicles are loaded with multiple selectively sorted proteins and nucleic acids. Although interest in the clinical potential of microvesicles is increasing, there is only limited understanding of different types of microvesicles and the mechanisms involved in their formation. Here, we describe what is presently known about this expanding and complex field of research focusing on the mechanism of biogenesis, cargo loading, and release of microvesicles.

FIGURE 1

Mechanisms of microvesicle formation at the cell surface and cargo delivery. (A) ARF6 regulates actomyosin contraction at the necks of nascent microvesicles via activation of ERK and Rho signaling pathways. Mutually antagonistic Rab35 and ARF6 signaling govern the intracellular localization of the actin bundling protein, fascin, which in turn modulates microvesicle pinching and release. Similarly, ARRDC1‐mediated recruitment of TSG‐101 from endosomes to the plasma membrane facilitates microvesicle the shedding and release. (B) ARF6‐regulated endosomes serve as a nexus integrating newly synthesized and recycling the protease MT1‐MMP for delivery to nascent microvesicles in a VAMP3‐dependent manner. (C) The pre‐miRNA transporter Exportin‐5 serves as a chaperone to link the movement of TMV pre‐miRNA cargo to the ARF6‐endosomal network. Upon exit from the nucleus, Exportin‐5 together with pre‐miRNA cargo, is shuttled to a trafficking complex of ARF6 and cytohesin‐3 (GRP1) for incorporation into shedding microvesicles. Additionally, O‐GlcNAcylation of the RNA‐binding protein hnRNPA2B1 in response to ROS‐mediated oxidative stress and ¹⁴Y‐phosphorylated Caveolin‐1 regulates the binding of a distinct miRNA repertoire. The resulting complex including bound miRNA then traffics to the plasma membrane where it is included within shed vesicles. Figure created with BioRender