Fig. 2
From: Exosomal transmission of viruses, a two-edged biological sword
Exo biogenesis via conventional ESCRT-dependent pathway (A). Conventional ESCRT-dependent strategy can lead sorting of four ubiquitinated cargos into ILVs. ESCRT machinery is composed of ESCRT-0, -I, -II, and -III. The recruitment of ESCRT-0 occurs on the cytoplasmic side of the endosomal membrane. ESCRT-0 complex consists of HRS and STAM subunits to recognize the ubiquitinated cargoes. The recruitment of ESCRT-0 is triggered via the interaction of the ESCRT-0 HRS subunit with PIP3 on the endosomal membrane. The interaction of ESCRT-0 HRS with clathrin proteins enhances the clustering of ESCRT-0 to endosomal membrane microdomains. To select exosomal cargo, ESCRT-0 provides a platform for the attachment of ESCRT-I. ESCRT-I consists of four subunits: TSG-101, Mvb12, VPS37, and VPS28. Interaction between ESCRT-0 HRS subunit with ESCRT-1 TSG-101 subunit leads to physical attachment of ESCRT-0 and ESCRT-1 on endosome membrane. ESCRT-0 and -I proteins provide a binding site for of ESRT-II complex (EAP45, EAP30, and two EAP20). The physical connection is done via the ESCRT-I VPS28 subunit and ESCRT-II EAP45 subunit. Interaction of ESCRT-I with ESCRT-II can induce invagination of the endosomal membrane. The complex of ESCRT-0, -I, and -II can induce the assembly and polymerization of ESCRT-III subunits (CHMP-1, -2, -3, -4, -5, -6, and -7). Interaction of EAP20 of ESCRT-II with CHMP6 of ESCRT-III promotes the recruitment of ESCRT-III subunits. The activation of ESCRT-III promotes a chain around the neck of intraluminal vesicles. Endosomal membrane curvature is stimulated by the interaction of Alix with Mvb12 and CHMP4 subunits of ESCRT-I and ESCRT-III, respectively. Upon ILV scission, Vps4-ATPase induces ESCRT-II subunits disassociation. Role of Syndecan-Syntenin-Alix in Exo biogenesis (B). Syndecan-Syntenin-Alix stimulates Alix-ESCRT-mediated sorting in Exo. Heparanase induces Syndecans clustering and facilitates its attachment to adaptor protein Syntenin via PDZ domains. Syntenin N-terminus connects to Alix via the direct interaction with V-domain. In the end, VSP4 is recruited by the ESCRT-III complex and leads a session of ILVs into MVB