New mechanism elucidated for essential molecule-sorting organelle

By Samantha Black, PhD, ScienceBoard editor in chief

November 15, 2019 -- A new study published in Nature Communications on November 15 suggests a new mechanism by which vesicles are transported out of the Golgi apparatus for the formation and maintenance of endosomes. The work, conducted by researchers from Tokyo University of Science and the Institute of Science and Technology in Austria, changes the paradigm of how materials are sorted and distributed once they enter cells.

The process by which cells internalize various cargo items through vesicles which bud from the cell membrane is termed endocytosis. Once inside the cell, the vesicle is quickly targeted by early endosomes for sorting, either for recycling or further processing. Previous research has shown that in yeast, the trans-Golgi network (TGN) has a role in endosomes endocytic pathways. The TGN is a majority sorting station for secretory proteins.

"We used our research to show that endocytic vesicle internalization is not essential, but that vesicle transport from the trans-Golgi network is crucial," say Jiro Toshima from the Department of Biological Science and Technology, Tokyo University of Science.

Ras-related protein (Rab5) is a GTP-binding protein involved in the recruitment of Rab7 proteins in early endosomes and the maturation of compartments to late endosomes. Rab7 is important in late endosome endocytic pathways. Specifically, Rab5 GTPase has been proposed to be a master regulator of endosome biogenesis and trafficking, playing an important role in endosome maturation.

The researchers explored the importance of the TGN and endocytosis on endosome formation in a series of experiments with mutated yeast strains and drugs (Brefeldin A and Monensin). From experiments with mutant yeast strains, they showed defective endosome formation. Rab5-mediated endosomal transport is not affected by endocytic internalization but rather is significantly reduced by the inhibition of post-Golgi traffic. It is, therefore, likely that post-Golgi traffic is of primary importance for endosomal formation. They found that endocytic vesicle internalization is not essential for Rab5-mediated endosome formation and transport from the endosome to the vacuole.

They also found that associated GTP-binding proteins, which are either resident in the Golgi or recruited to it, are transported from the Golgi to the endosomes where they activate Rab5 and spark the formation of endosomes. This led them to conclude that endosome formation depends on a process that starts at the TGN. Rab5 GEF Vps9p is first recruited to the TGN and then transported to the endosomal compartments where it activates Vps21p. They demonstrated with their gene deletion studies that vesicle transport from the TGN is crucial for Vps21p-mediated endosome formation.

The team suggests that the endocytic pathway might be only required for the transport of cargo from the cell membrane to the TGN or for vesicles budding off from the TGN membrane, but not endosome formation.

"Our results provide a different view of endosome formation and identify the TGN as a critical location for optimal maintenance and functioning of endosomes," Toshima says.

The results of this study are only scratching the surface of the underlying mechanisms that control endosomes. Given that exosomes are essential to cell function, adding to existing knowledge of core pathways will help researchers gain a deeper comprehension of the molecular basis of diseases involving defective endosomes and develop more effective therapies.

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