Table 2.
Composition and function of complexes and key enzymes related to exosome biogenesis, sorting, transport and secretion.
| Complexes | Subunits | Localization | Function | References |
|---|---|---|---|---|
| ESCRT | ESCRT-0 (HRS, STAM) |
MVBs | Recognizes and binds ubiquitinated proteins and sorts them into spatially restricted areas on the endosomal membrane; HRS recognizes the mono—ubiquitinated proteins and recruits TSG101 | (26, 29, 42) |
| ESCRT | ESCRT-1 (TSG101, VPS28, VPS37, MVB12), ESCRT2 (VPS36, VPS22, VPS25) | MVBs | Regulates the initial deformation of membrane into buds with sequestered cargo and may be involved in cargo transfer | (26, 29, 42) |
| ESCRT | ESCRT-3 (VPS2, VPS20) | ILV, MVBs | Drives membrane invagination and separation, and subsequent vesicle scission | (26, 29, 42) |
| AAA ATPases | VPS4 | ILV | Interact with ESCRT-3 to cause constriction and scission of ILV | (29) |
| ESCRT-associated protein | ALIX | ILVs, MVBs | Controls exosomal cargo incorporation and regulates sorting of PD-L1 onto ILVs; ALIX and syntenin-ALIX complex stimulate intraluminal budding | (24, 30) |
| Rabs | Rab5 | Early endosomes, PM | Mediates endocytosis and generation and maintenance of early endosomes | (21, 22) |
| Rabs | Rab7 | MVBs | Mediates maturation and trafficking of MVBs to lysosomes | (21) |
| Rabs | Rab27a | MVBs | Involved in the fusion of MVBs to the PM | (13, 25) |
| Rabs | Rab27b | MVBs | Promotes formation and stability of MVB docking and facilitates exosome shedding | (20, 25) |
| Rabs | Rab35 | MVBs | Controls MVB transport and influences the docking process | (34) |
| SNAREs | v-SNARE, t-SNARE, |
Widespread distribution in the endosomal system | Drive membrane fusion and mediate fusion of MVBs with the PM | (34, 39) |
| Enzyme | Heparanase | Endosome membrane, PM | Exogenous heparanase impacts intraluminal budding and, therefore, exosome biogenesis | (24) |
| Enzyme | nSMase2/SMPD3 | PM, endosomes | Regulates biosynthesis of ceramide and promotes budding of intravesicular vesicles | (13, 40) |
ESCRT, endosomal sorting complexes required for transport; HRS, hepatocyte growth factor receptor substrate; TSG101, tumor susceptibility gene 101 protein; STAM, signal transducing adaptor molecule; MVB, multivesicular bodies; PM, plasma membrane; VPS, Vacuolar protein sorting homolog; ALIX, ALG2-interacting protein X; Rabs, RAS related proteins; TGN, trans Golgi network; SNARE, soluble N-ethylmaleimide-sensitive fusion factor attachment protein receptor; nSMase2, neutral sphingomyelinase 2; SMPD3, Sphingomyelin Phosphodiesterase 3.