Fig. 3

The biogenesis and release mechanisms of exosomes during apoptosis. Classical: The components of the endosomal sorting complex required for transport (ESCRT) actively participate in the formation of exosomes, a pivotal process in intracellular transport. The ESCRT-0 complex, characterized by the abundant HRS-STAM heterotetramer, 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). Apoptosis: In ER stress-induced apoptosis, LSEs can recognize and encapsulate misfolded proteins within the endoplasmic reticulum. In exogenous apoptosis, membrane receptors such as tumor necrosis factor receptor 1 (TNFR1), death receptors, or Toll-like receptors (TLRs) are activated, resulting in the recruitment of the TNFR1-associated death domain (TRADD) or Fas-associated death domain (FADD), which interact with procaspase 8/10 to form the death-inducing signaling complex (DISC). Cleavage of procaspase 8/10 activates caspase 3/7, promoting LSE formation and cargo sorting, which are encapsulated within the endosomal lumen. In endogenous apoptosis, BAK and BAX activate proteins to form pores in the mitochondrial outer membrane, releasing Cyt C into the cytosol. Free Cyt C binds Apaf-1, activating pro-caspase 9 and forming the apoptosome complex. Caspase-9 is activated within the apoptosome to further activate caspase 3/7. Cyt C, Apaf-1, and activated caspase 3/7 can all facilitate late endosome formation and sequestration into the endosomal lumen. Ultimately, LSEs fuse into MVBs. With the assistance of the ESCRT-III complex, these MVBs release exosomes into the extracellular matrix by fusing with the plasma membrane. Additionally, apoptotic bodies are released during apoptosis. (Black arrows: involved in apoptotic mechanisms; purple arrows: involved in exosome biogenesis; curved purple arrows: involved in the formation of exosome cargo)