Model for the involvement of GPA-labeled endosomes in the exocytosis of autophagocytosed cytoplasmic content during reticulocyte maturation. (A) Autophagosomes derive from isolation membranes (i) that expand to engulf organelles and other cytoplasmic content before sealing (ii). Fusion of autophagosomes with late endosomes generates amphisomes (iii). As a prelude to fusion, autophagosomes lose LC3 from their outer membrane (a process known as delipidation), meaning that LC3 is found only on the inside of the resultant amphisome. During reticulocyte maturation, active endocytosis of GPA is observed (v), and these endosomes (vi) converge with LC3-positive amphisomes to generate an LC3/GPA–positive hybrid organelle (vii) that has the capacity to fuse with the plasma membrane (viii). Exocytosis may occur at sites of weakened underlying skeleton and is predicted to release cytoplasmic content concomitant with delivering GPA back on to the plasma membrane. (B) The above model predicts that plasma membrane surface area would increase as a result of internal vesicle maturation and exocytosis. We postulate, therefore, that the exocytic event is coupled with a process of plasma membrane blebbing, facilitated in vivo by passage through the spleen. By coupling these events, integral membrane proteins of the exocytic vesicle (including GPA) would be incorporated stochastically into the nascent bud, thereby effecting the shedding of redundant material that had previously been enriched in endosomes.