Figure 2.

Megalin-mediated endocytosis and megalin trafficking. The plasma membranes start to invaginate and at last bud off during endocytic internalization and reach early endosomes, where the decision for further ligand processing is made depending on the cargo content. In the absence of ARH, megalin is recycled back to the plasma membrane via the early recycling pathway, whereas in the presence of ARH, megalin is recycled back to the membrane via the late recycling pathway. Depending on the specific protein interactions and domain-based sorting processes, early endosomes may also be directed to late endosomes, which then matures into a late endosomal compartment and forms multivesicular bodies. When multivesicular bodies come into contact with the plasma membrane, their contents are secreted in the form of exosomes. Megalin ligands may be subjected to lysosomal degradation and the metabolized ligands then undergo basolateral transcytosis. Megalin also undergoes regulated intramembrane proteolysis (RIP) and is shedded from plasma membrane.