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Context-specific regulation of extracellular vesicle biogenesis and cargo selection

Nature Reviews Molecular Cell Biology volume 24, pages 454–476 (2023)Cite this article

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Abstract

To coordinate, adapt and respond to biological signals, cells convey specific messages to other cells. An important aspect of cell–cell communication involves secretion of molecules into the extracellular space. How these molecules are selected for secretion has been a fundamental question in the membrane trafficking field for decades. Recently, extracellular vesicles (EVs) have been recognized as key players in intercellular communication, carrying not only membrane proteins and lipids but also RNAs, cytosolic proteins and other signalling molecules to recipient cells. To communicate the right message, it is essential to sort cargoes into EVs in a regulated and context-specific manner. In recent years, a wealth of lipidomic, proteomic and RNA sequencing studies have revealed that EV cargo composition differs depending upon the donor cell type, metabolic cues and disease states. Analyses of distinct cargo ‘fingerprints’ have uncovered mechanistic linkages between the activation of specific molecular pathways and cargo sorting. In addition, cell biology studies are beginning to reveal novel biogenesis mechanisms regulated by cellular context. Here, we review context-specific mechanisms of EV biogenesis and cargo sorting, focusing on how cell signalling and cell state influence which cellular components are ultimately targeted to EVs.

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Fig. 1: A road map of extracellular vesicle biogenesis.
Fig. 2: Mechanisms of extracellular vesicle biogenesis and cargo sorting.
Fig. 3: Examples of context-specific regulation of cargo sorting.

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Acknowledgements

The authors thank the members of the Weaver and Di Vizio groups for many helpful discussions. Funding support came from NIH/NSF grants (R01CA206458, R01CA249684, P01CA229123, R01CA249424, U54 CA217450, U01CA224276 and NSF-2036809 to A.M.W.) and from NIH/NCI (R01CA234557 and R01CA218526 to D.D.V.). A.C.D. was also supported by a NIH T32 training grant (1T32GM137793-01) and NSF GRFP #1937963. Any opinions, findings and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation or the National Institutes of Health.

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Authors and Affiliations

  1. Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA

    Andrew C. Dixson, T. Renee Dawson & Alissa M. Weaver

  2. Center for Extracellular Vesicle Research, Vanderbilt University School of Medicine, Nashville, TN, USA

    T. Renee Dawson & Alissa M. Weaver

  3. Department of Surgery, Division of Cancer Biology and Therapeutics, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Dolores Di Vizio

  4. Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA

    Alissa M. Weaver

Authors
  1. Andrew C. Dixson
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  2. T. Renee Dawson
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  3. Dolores Di Vizio
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  4. Alissa M. Weaver
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Contributions

A.C.D. and T.R.D. researched data for the article and wrote the majority of the initial manuscript. D.D.V. and A.M.W. researched data for the article and also wrote sections of the manuscript. A.C.D. drafted the figures with input and edits from T.R.D., A.M.W. and D.D.V. T.R.D. drafted the tables with input and edits from A.C.D., D.D.V. and A.M.W. All authors contributed substantially to discussion of the content. All authors reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Alissa M. Weaver.

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Nature Reviews Molecular Cell Biology thanks Deborah Goberdhan, Clotilde Théry and Pascale Zimmermann who co-reviewed with Lukas Hyka for their contribution to the peer review of this work.

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Supplementary information

Glossary

Argonaute 2

(AGO2). The central component of the RNA-induced silencing complex. AGO2 is guided by a microRNA to the open reading frame or 3′ untranslated region of a target mRNA, where it recruits other factors for translational silencing, depolyadenylation and/or degradation of the target mRNA. Alternatively, AGO2 activates its ‘slicer’ (endonuclease) activity when directed to an mRNA target by an exogenous small interfering RNA that is perfectly complementary to the target mRNA.

BAR domain

BIN, amphiphysin and Rvs161 and Rvs167 domain; a conserved protein domain that promotes and/or senses positive membrane curvature. Conversely, inverse BAR domains associate with negatively curved membranes.

Blebs

Bulbous protrusions of plasma membrane that form when the cortical cytoskeleton decouples from the plasma membrane.

Circular RNAs

Single-stranded RNAs that arise when the 3′ end of one exon back-splices to its own 5′ end or the 5′ end of another exon.

ERK

Extracellular-signal-regulated kinase, also known as mitogen-activated protein kinase (MAPK); an oncoprotein and serine/threonine-protein kinase activated by epidermal growth factor receptor (EGFR) and RAS–RAF–MEK signalling.

ERM proteins

Ezrin, radixin and moesin proteins; proteins that link the actin cytoskeleton to transmembrane proteins in the plasma membrane, playing roles in cytoskeleton organization at the cell cortex and in signal transduction.

ESCRT

Cargo sorting, membrane remodelling and scission machinery made up of four cytosolic protein complexes, known as ESCRT-0, ESCRT-I, ESCRT-II and ESCRT-III, which work alongside a fifth complex containing the VPS4 ATPase.

EWI proteins

A subfamily of immunoglobulin proteins containing an extracellular Glu-Trp-Ile (EWI) motif.

Focal adhesion kinase

(FAK). A tyrosine kinase activated by integrin and growth factor signalling that controls the actin cytoskeleton to influence cell shape, focal adhesion assembly and disassembly, and cell migration.

Gasdermin D

Effector of pyroptosis activated by caspase 1-mediated proteolytic cleavage downstream of the inflammasome. Cleaved gasdermin D forms pores in the plasma membrane and organelle membranes, resulting in cell death.

Glycocalyx

From Greek, meaning sweet husk; a tough casing consisting of glycoproteins, proteoglycans and glycolipids that covers a cell.

Hyaluronan

A long, linear polymer of disaccharides that forms a part of the extracellular matrix and resists compression.

Hypoxia-inducible factor 1α

(HIF1α). A transcription factor activated under low-oxygen conditions that regulates angiogenesis, apoptosis and many other cellular processes.

Inflammasome

A high molecular weight protein complex that activates pyroptosis, a pro-inflammatory and lytic type of programmed cell death, especially in response to infection.

Leptin

A hormone secreted by fat cells that regulates hunger and body mass.

Lipopolysaccharide

A potent immunostimulatory glycolipid present on the outer membrane of Gram-negative bacteria.

Major histocompatibility complex class II

(MHC-II). A transmembrane protein complex found on antigen-presenting cells that binds to exogenous antigen peptides and presents these peptides to immune cells.

Membrane contact sites

Regions where two organelle membranes are tethered together (typically at a distance of ~10–40 nm) to perform a function other than fusion.

Membrane trafficking

The process of sorting molecular cargoes, especially lipids and proteins, into different compartments within the cell.

Myristic acid

A saturated fatty acid with 14 carbons (14:0).

Nonalcoholic steatotic hepatitis

A chronic, severe inflammatory liver disease caused by metabolic alterations associated with obesity and typified by fat accumulation in the liver.

Palmitic acid

A saturated fatty acid with 16 carbons (16:0).

PD-L1

A ligand that activates its receptor (PD-1) on T cells to inhibit T cell activation.

Reticulocytes

Nucleated precursor cell type to red blood cells.

ROCK

RHO-associated coiled-coil-containing protein kinase that acts downstream of the small GTPase RHOA in cytoskeleton remodelling and membrane blebbing.

Small nucleolar RNAs

RNAs that function to perform direct covalent modification of ribosomal RNAs, small nuclear RNAs and other RNAs. Two classes of small nucleolar RNAs include C/D box small nucleolar RNAs, which direct 2′-O-ribose methylation, and H/ACA box small nucleolar RNAs, which direct pseudouridylation.

SRC

Membrane-associated non-receptor tyrosine kinase that localizes to endosomes and regulates exosome biogenesis and cargo sorting.

Tetraspanins

A conserved family of four-pass transmembrane proteins that organize lipid and signalling domains in membranes. Tetraspanins are enriched in many extracellular vesicles (EVs) and in some cases regulate EV biogenesis.

Warburg effect

The tendency of cancer cells to upregulate glucose uptake and aerobic glycolysis.

Y-RNA

A subtype of RNA transcribed by RNA polymerase III that is conserved among vertebrates but has poorly understood functions. Four Y-RNA genes are present in humans.

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Dixson, A.C., Dawson, T.R., Di Vizio, D. et al. Context-specific regulation of extracellular vesicle biogenesis and cargo selection. Nat Rev Mol Cell Biol 24, 454–476 (2023). https://doi.org/10.1038/s41580-023-00576-0

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