Fig. 5

The biogenesis and release mechanisms of exosomes during autophagy. Classical: The ESCRT-0 complex initiates intracellular sorting and recruits ESCRT-I. Collaboratively, ESCRT-I and ESCRT-II orchestrate membrane invagination, giving rise to early endosomes (ESEs). These ESEs undergo mutual fusion, maturing into late endosomes (LSEs). Autophagy: During autophagy, the activation of ULK1, FIP200, and various ATG proteins leads to the formation of the ULK1 complex. This complex phosphorylates and binds to the PI3KC3 complex, initiating the activation of phosphatidylinositol-3-phosphate (PI3P) and recruiting ATG family proteins. Consequently, ATG proteins not only bind to membrane-resident phosphatidylethanolamine (PE) to catalyze the phospholipidation of LC3-I but also facilitate the formation of late endosomal structures (LSEs) and cargo sorting. These structures are eventually encapsulated by late endosomes. Ultimately, LSEs fuse into multivesicular bodies (MVBs), and MVBs undergo budding to release exosomes through ATG-mediated ESCRT-III phosphorylation and membrane invagination. In addition to exosomes, autophagosomes are also released during autophagy. (Black arrows: involved in autophagy mechanisms; purple arrows: involved in exosome biogenesis; curved purple arrows: involved in the formation of exosome cargo)