Table 1.
Molecules involved in EV formation and their effects.
| Molecules | Type | Effects | Ref. |
|---|---|---|---|
| ESCRT-0 (HRS, HGS, STAM1, VPS28) | complex | Binding and sequestering ubiquitinated cargo through ubiquitin-binding motifs | [37,38] |
| ESCRT-I (TSG101, VPS37A) | complex | Sorting ubiquitinated cargo into ILVs of MVEs; participating membrane budding into the lumen of the MVBs | [38,39] |
| ESCRT-II(SNF8, VPS25, VPS36) | complex | Sorting and sequestering ubiquitinated cargo proteins; participating membrane budding with ESCRT-I; modulating the assembly of ESCRT-III helices | [39,40] |
| ESCRT-III (CHMPs) | complex | Driving membrane neck constriction on MVBs during ILV formation with joint effect of Vps4 | [41] |
| Rab5 | GTPase | Participating in endosome fusion to form ESEs | [42] |
| Rab7 | GTPase | Mediating trafficking LSEs | [42] |
| Rab9 | GTPase | Participating in assembly of cargo coats and vesicle budding | [43] |
| Rab11 | GTPase | Docking/tethering of MVBs and promoting Ca2+-dependent homotypic fusion process | [44] |
| Rab27a | GTPase | Regulating the size of MVBs | [45] |
| Rab27b | GTPase | Functioning in docking and fusion with PM against redistributing MVBs to perinuclear region | [45] |
| * Rab31 | GTPase | Driving ILV formation by binding with flotillin proteins to make EGFR enter MVEs; suppressing MVE degradation | [46] |
| Rab35 | GTPase | Regulating PIP2 levels of PM; docking/tethering MVBs | [47] |
| Rab39 | GTPase | Interacting with effector UACA, recruiting Lyspersin to mediate basolateral exosome release | [48] |
| RAL(RAL-1, RalA, RalB) | GTPase | Driving the fusion between MVBs and PM | [49] |
| TBC1D10A-C | GTPase-activating protein | Acting on Rab35 to regulate exosome secretion | [50] |
| Ca2+ | ions | Acting in homotypic fusion | [44] |
| SNAREs (syntaxin-4, syntaxin-5, SNAP-23, and VAMP-7) | soluble N-ethylmaleimide-sensitive factor attachment protein receptors | Driving the fusion between MVBs and PM | [49,51] |
| ALIX | scaffold proteins | Interacting with ESCRT-I (subunit TSG101) and ESCRT-III (subunit CHMP4) and participating in cargo sorting and ILV formation | [52] |
| Heparanase | / | Regulating the syndecan-syntenin-ALIX pathway through cleaving heparan sulfate chains on syndecans, thus facilitating endosomal membrane budding and exosome formation | [53] |
| Syntenin | membrane scaffold proteins | Interacting with ALIX and contributing to intraluminal budding of endosomal membranes | [54] |
| Syndecan | membrane scaffold proteins | Recruiting syntenin-ALIX and facilitating membrane budding to form ILVs and exosomes through the syndecan-syntenin-ALIX pathway | [54] |
| ARF6 and PLD2 | / | Controlling the budding of ILVs into MVBs through ALIX–syntenin | [55] |
| DGKα and PKD1/2 | / | Regulating MVB maturation and polarized traffic | [56] |
| CD81, CD63, CD9 | tetraspanins; exosome cargo proteins | Facilitating the trafficking and oligomerization of other membrane proteins | [57] |
| PE, PS, PA, and lysophospholipid | phospholipids | Promoting exosome biogenesis | [58] |
| KIBRA | scaffolding protein | Preventing Rab27a from being ubiquitinated and regulating exosome secretion | [59] |
| * Neutral sphingomyelinase 2 (nSMase2) | sphingomyelinase | Producing ceramide to achieve ESCRT-independent budding machinery | [60] |
| * Ceramide | / | Improving membrane curvature and regulating the abundance of other lipids, playing a key role in ESCRT-independent budding machinery | [60] |
| * LAMP2A | membrane protein | Loading proteins (such as HIF1A) into exosomes | [61] |
The abbreviations above are explained as follows: PM: plasma membrane; ESEs: early sorting endosomes; LSEs: late sorting endosomes; MVBs: multivesicular bodies; ILVs: intraluminal vesicles; ESCRT: endosomal sorting complex required for transport; ALIX: apoptosis-linked gene 2-interacting protein X; PE: phosphatidylethanolamine PS: phosphatidylserine; PA: phosphatidic acid; EGFR: epidermal growth factor receptor; SNAREs: soluble N-ethylmaleimide-sensitive factor attachment protein receptors; ARF6: small GTPase ADP ribosylation factor 6; PLD2: phospholipase D2; DGKα: diacylglycerol kinase α; PKD: protein kinase D. * annotate the molecular involving ESCRT-independent mechanism.