18.5:
The Early Endosome: Endocytosis of Transferrin
The early endosome is a dynamic organelle that functions as the main sorting station and determines the fate of any incoming macromolecule which enters a cell in an endocytic vesicle. Transferrin – a protein that facilitates iron uptake in the cell enters through this pathway.
Transferrin binds to iron, forming a complex called ferrotransferrin. Once ferrotransferrin binds to its receptor present on the cell surface, it is internalized by receptor-mediated endocytosis.
The endocytosed vesicle, containing the ferrotransferrin-receptor complex, loses its clathrin coating and fuses with the early endosome. Then, the acidic environment of the early endosome causes iron to be released from transferrin .
The released iron exits through a channel and later can be incorporated into hemoglobin or bind to iron-storage proteins, such as ferritin. The iron-free transferrin, also known as apotransferrin, remains bound to its receptor.
The apotransferrin-receptor complex enters the early endosome's tubular domain, from where it is recycled back to the plasma membrane. Once outside the cell, apotransferrin detaches from its receptor to bind to more incoming iron.
18.5:
The Early Endosome: Endocytosis of Transferrin
Essential proteins such as insulin or low-density lipoprotein (LDL) and micronutrients such as iron enter a eukaryotic cell through receptor-mediated endocytosis. Subsequently, the early endosomes fuse with the vesicles containing such receptor-ligand complexes and play a vital role in sorting the incoming ligands and receptors. While the ligands are either degraded inside the vesicle or released into the cytosol, their receptors are returned to the plasma membrane for further rounds of endocytosis.
Early endosomes have a membrane enriched in phosphatidylinositol 3-phosphate, also known as PtdIns(3)P, which regulates almost all sorting events in the early endosome along with two Ras-associated binding proteins or Rab proteins. Rabs localized in the early endosome, namely Rab4 and Rab5, are GTP-binding proteins that are active when bound to GTP and inactive when bound to GDP. Rab5 is extensively studied for several functions that it regulates, such as entry of endocytosed material into early endosomes, generation of phosphatidylinositol 3-phosphate, and movement of early endosomes along the microtubules. Rab4 regulates the recycling of receptors from the early endosome to the plasma membrane.
Improper protein sorting in the early endosome or loss of regulatory control in the sorting process can cause aberrant endosomal functions, leading to various neurological conditions such as Alzheimer’s disease, Huntington’s disease, or Down’s syndrome.
Despite the several important roles early endosomes play, their fundamental characteristics are not yet fully understood. For example, the mechanisms underlying the selection of specific Rab proteins for localization into the early endosomes are still unknown. It is also unclear if different early endosomes are involved in the sorting of different types of receptors. Additionally, early endosomes do not have distinct membrane markers that can be easily identified through light microscopy, making it difficult to distinguish them from other types of endosomes. Therefore, early endosomes are a yet-evolving topic of investigation.
Suggested Reading
- Alberts, Bruce, et al. Molecular Biology of the Cell. 6th ed. Garland Science, 2015. pp 733-735.
- Jovic M., Sharma M., Rahajeng J. and Caplan S. The early endosome: a busy sorting station for proteins at the crossroads. Histol Histopathol (2010), 25(1):99-112.
- Naslavsky, N., and Caplan, S. The enigmatic endosome–sorting the ins and outs of endocytic trafficking. Journal of cell science (2018), 131(13).