Table 1.
Selection of Key Proteins in Extracellular Vesicle Biogenesis and Lipid Signaling.
| Protein Complex or Protein | Role | References |
|---|---|---|
| ESCRT | Targets endosomes to a pathway | [11,194] |
| ESCRT-0 (with Hrs) | Recognizes ubiquitinylated cargo and sorts to PI3P rich vesicles | [9] |
| ESCRT-1 | With ESCRT-2, generates membrane budding inward in endosomes to form intraluminal vesicles, recruits ESCRT-0-ubiquitin domains to buds | [195] |
| ESCRT-2 | With ESCRT-1, generates membrane budding inward in endosomes to form intraluminal vesicles, recruits ESCRT-0-ubiquitin domains to buds | [195] |
| ESCRT-3 | Cleaves membrane buds to form intraluminal vesicles | [195] |
| Vacuolar protein sorting (Vps)4 | Interacts with ESCRT I-III and oxysterol-binding protein; may regulate facilitate miRNAs in exosomes that modulate PI3K/Akt pathway | [22,23,196] |
| TSG101 | ESCRT machinery protein, interacts with ARRDC1, participates in multivesicular body sorting via binding with ALIX, mediates the release of microvesicles containing TSG101, ARRDC1 and other cellular proteins | [15,197] |
| Arrestin domain-containing protein 1 (ARRDC1) | Interacts with TSG101, mediates the release of microvesicles containing TSG101, ARRDC1, mitochondrial proteins and other cellular proteins; mediates release of exosomes containing proteins implicated in apoptosis | [15,198] |
| Charged multivesicular body protein (CHMP) | Participates in multivesicular body sorting via binding with ALIX | [197] |
| Rab GTPases | Transport of endosomes | [9] |
| Rab11 | Targets multivesicular body to plasma membrane for fusion and exosome release | [10,199] |
| Rab27 | Targets multivesicular body to plasma membrane for fusion and exosome release | [10,200] |
| Rab35 | Targets multivesicular body to plasma membrane for fusion and exosome release | [10,201] |
| Rab22A | Selective recruitment of proteins to microvesicles under hypoxic conditions | [16] |
| Alg2-interacting protein X (Alix) | Recruited to endosomal membrane via domain that binds BMP; with LBPA, induces formation of endosome membrane invaginations; participates in multivesicular body sorting via binding with TSG101 and CHMP4, interacts with syntenin to support intraluminal vesicle budding | [197,202,203] |
| Acid ceramidase | Converts ceramide to sphingosine and fatty acids in lysosomes; inhibition increases exosome release | [38,204] |
| ADP-Ribosylation Factor 6 (ARF6) | GTPase; activates phospholipase D2 & PIP5K; interacts with syntenin; regulates intraluminal vesicle budding and exosome production; regulates selective recruitment of proteins into microvesicles | [14,203,205] |
| ATP-binding cassette transporter A3 | Reduces exosome formation; mediates transport of choline-phospholipids into intracellular vesicles (possible connection to exosome formation?) | [206,207] |
| Diacyl glycerol (DAG) kinase a | Catalyzes conversion of DAG to phosphatidic acid; inhibits exosome secretion (by reducing DAG levels) | [208] |
| Flotillins | Modify exosomal cargo | [34,41] |
| Phosphatidylinositol 4-phosphate 5-kinase (PIP5K) | Catalyzes phosphatidylinositol 4-phosphate (PI4P) phosphorylation to form phosphatidylinositol 4,5-bisphosphonate (PI4,5P2), Activated by ARF6 and phosphatidic acid | [209] |
| Phospholipase D2 | Catalyzes hydrolysis of phosphatidylcholine to produce phosphatidic acid; involved in formation of exosomes with syntenin, ALIX, CD63, regulator of intraluminal vesicle budding and exosome production | [205,210,211] |
| PIKfyve | converts PI3P to either PI(3,5)P2 or PI5P | [20] |
| Sorting nexin proteins (SNX) | Interact with PI3P and enable transport to trans-golgi or plasma membrane | [20] |
| Sphingomyelinases (SMase) | Hydrolyze sphingomyelins to produce ceramide | [24] |
| Syndecans | Ubiquitous transmembrane proteins, enriched in CD63+, flotillin-1- exosomes, bind with syntenin, likely recruit syntenin-ALIX and support membrane budding | [203] |
| Syntenin | Interacts with ALIX, syndecans to support formation of intraluminal vesicles | [203] |
| Tetraspanins | Participate in exosome biogenesis; interact with other transmembrane receptors, within themselves and with integrins and other proteins; often form tetraspanin-enriched microdomains | [40] |
| Vps24 | Binds with PI(3,5)P2 to target endosomes to EVs | [20] |