Figure 1. Key Figure: Overview of degradative and secretory roles of ATG8 proteins described in this review.

ATG8s (green circles) incorporate into intracellular vesicles with degrative fate, including autophagosomes (Panel A) and diverse vesicles of endosomal origin (Panels B and C). During macroautophagy (Panel A), ATG8s associate with the outer- and inner membrane of autophagosomes via canonical conjugation mechanisms (orange text boxes). In the inner membrane, ATG8s interact with receptors to recruit cytosolic cargo, such as defective mitochondria and protein aggregates. On the outer membrane, ATG8s bind adaptor proteins that bring the transport and fusion machinery, allowing directional retrograde transport of autophagosomes and fusion with lysosomes for cargo degradation. Via non-canonical conjugation mechanisms (purple boxes), ATG8 also incorporate into phagosomes containing components of extracellular origin such as bacteria or apoptotic bodies (Panel B). During this process, called LC3-associated phagocytosis (LAP) ATG8s associate to the cytosol-facing part of the membrane and may play roles in fusion and transport for lysosomal degradation. In addition, ATG8s associate to multivesicular bodies (MVB) to recruit receptors and facilitate cargo degradation in a process called endosomal microautophagy (eMI). Interestingly, ATG8s can also associate with secretory vesicles: small extracellular vesicles and secretory autophagosomes, via potentially non-canonical and canonical conjugation machineries, respectively. Within MVB, ATG8s participate in the inward budding of small extracellular vesicles and recruit RNA-binding proteins by direct interaction, to allow their subsequent secretion upon fusion of the MVB with the plasma membrane, during a process called LC3-dependent extracellular vesicle loading and secretion (LDELS) (Panel D). Within secretory autophagosomes, ATG8s may mostly participate in the recruitment of specific transport and fusion machinery, which can facilitate directional anterograde trafficking towards the plasma membrane for fusion and cargo release to the extracellular media. Some cargo, such as IL-1β can be incorporated in between the inner- and outer membranes of autophagosomes for unconventional secretion (Panel E). Finally, ATG8s incorporate into amyloid-β-containing endosomes (Panel C). During LC3-associated endocytosis (LANDO), endosomes containing amyloid-β are endocytosed (1), then amyloid-β is delivering to lysosomes for degradation (2) and finally fusion of endosomes with the plasma membrane allows the recycling of amyloid-β receptor back to the cell surface (3). See text for further details.