Figure 9.

A graphic model for the roles of RAB21 in retromer-mediated cargo sorting. In WT cells, the retromer mediates the recycling of membrane proteins such as SLC2A1 from endosomes to the plasma membrane with the assistance of RAB21, ensuring efficient glucose uptake. The retromer is also in charge of the retrograde transport of receptor proteins such as IGF2R from endosomes to the TGN for continuous delivery of hydrolases to lysosomes and maintenance of lysosome function. RAB21 depletion prevents the dissociation of retromer-decorated tubules from endosomes, disrupts endosome to plasma membrane recycling of SLC2A1 and mis-sorts SLC2A1 to lysosomes for degradation, thereby affecting glucose uptake and activating the AMPK-ULK1 pathway and autophagic flux. Meanwhile, trafficking between endosomes and the TGN is likely strengthened, rendering IGF2R more efficient in delivering lysosomal hydrolases such as CTSB, thereby increasing lysosome activity.