FIGURE 2.

Processes occurring within the maturing circulating reticulocyte. Once enucleated, the newly formed reticulocyte migrates to the peripheral blood where it completes its maturation in a surrounding eliciting external forces, shear stress and capillary/splenic interactions. Three major events occurring are volume control, membrane remodeling and vesicularization. As for volume control, a key role is played by ion channels KCNN4 (or Gardos), Piezo1 and KCC1 (see text). During reticulocyte maturation an active membrane remodeling is also occurring, in which the two main red blood cells complexes, the ankyrin and the junctional complexes (linked through a cytoskeleton network) are involved (see text). Lastly, the reticulocyte makes use of the ESCRT- mediated multi vesicular body (MVB) machinery to expel unwanted proteins. Proteins, e.g., TFR1 and Aquaporin1 are ubiquitinated and routed to the MVB where the ESCRT complex (in particular its associated protein Alix and Hsp60) contributes in assembling the MVB; this process will result in exosome releasing, which is also described to be triggered by calcium influx (see text). All three processes are mechanistically linked (see text) and need to occur in order for a reticulocyte to mature to an erythrocyte.