Exosome biogenesis and release machinery

The exosome biogenesis and release machinery is a complex network of proteins and lipids responsible for the formation and secretion of small extracellular vesicles (30-150 nm) known as exosomes (Kalluri & LeBleu, 2020, Science). This process primarily involves the Endosomal Sorting Complex Required for Transport (ESCRT), which facilitates the inward budding of the endosomal membrane to create multivesicular bodies (MVBs), and ESCRT-independent mechanisms involving ceramide production by neutral sphingomyelinase 2 (nSMase2) (Trajkovic et al., 2008, Science). Once formed, MVBs are transported to and docked at the plasma membrane by Rab GTPases, such as Rab27a and Rab27b, before being released via SNARE-mediated fusion (Ostrowski et al., 2010, Nature Cell Biology). In oncology, this machinery is frequently upregulated, allowing cancer cells to release exosomes that promote pre-metastatic niche formation and immune evasion (Peinado et al., 2012, Nature Medicine). In neurodegenerative disorders, the machinery facilitates the trans-synaptic spread of pathological proteins like tau and alpha-synuclein (Asai et al., 2015, Nature). Pharmacological inhibitors like GW4869 target nSMase2 to reduce exosome production, while drugs like Manumycin A target the Rab-mediated secretion steps (Menck et al., 2017, J Extracell Vesicles). Despite its therapeutic potential, the broad physiological role of exosomes in normal cell-to-cell communication poses significant challenges for achieving target specificity and avoiding systemic toxicity (Wiklander et al., 2019, Science Translational Medicine).

Other names

Extracellular vesicle biogenesis pathwayExosome secretion machineryMVB formation and secretion pathwayESCRT-dependent and independent secretion pathways

Inhibition of neutral sphingomyelinase 2 (nSMase2) to block ceramide-dependent budding, and inhibition of Rab GTPases (e.g., Rab27a/b) to prevent vesicle docking at the plasma membrane (Kalluri & LeBleu, 2020; Ostrowski et al., 2010).