Fig. 2

ESCRT-dependent and ESCRT-independent exosome biogenesis. ESCRT-dependent exosome biogenesis (upper side): ESCRT-0 recognizes ubiquitinated cargo and binds it to the endosomal membrane [12]. ESCRT-0 recruits ESCRT-I, which along with ESCRT-II stabilizes the neck of the forming vesicle. Subsequently, ESCRT-III narrows the neck [13]. At this stage, the cargo is deubiquitinated [14]. Upon recruitment of the Vps4-Vga1 complex, the scission of the vesicle neck by ESCRT-III begins, and ultimately ESCRT-III is disassembled [13]. For detailed information on the individual subunits of ESCRT, refer to Henne et al. [14] and Williams et al. [15]. ESCRT-independent exosome biogenesis (lower side): a nSMase2 catalyzes the conversion of sphingomyelin to ceramide. It is hypothesized that cone-shaped ceramide accumulates locally, leading to the formation of ceramide-enriched microdomains that induce membrane curvature [8, 10, 16]. b Ceramide is metabolized to sphingosine, which is subsequently converted to sphingosine-1-phosphate (S1P). S1P is involved in the sorting of cargo into ILVs. S1P activates the S1P receptor, which helps in the maturation of MVBs [9]. c Rab31 sorts epidermal growth factor receptor (EGFR) into ILVs [10]. Rab31 recruits TBC1D2B, reducing the activity of Rab7 and inhibiting the fusion of MVBs with lysosomes. As a result, the inhibition of Rab7 promotes exosome secretion [11]. SM, sphingomyelin; Cer, ceramide; Sph, sphingosine; S1P, sphingosine-1-phosphate