Mannose 6-phosphate Receptor - Recycling To The Trans-Golgi Network

Recycling To The Trans-Golgi Network

The return route taken by MPRs to the TGN has been somewhat controversial. Because depletion of AP1 or so-called retromer proteins results in MPR sequestration in early endosomes, many have concluded that the MPR traffics directly from early endosomes to the TGN. The bacterial shiga toxin and cholera toxins use such a pathway while TGN46 recycles back to the Golgi via recycling endosomes. However, MPRs bind their ligands in a pH dependent manner and need a pH < 6 to dissociate the ligand from the MPR. The pH of the early endosome has been measured to be between pH 6.2-6.3, while the pH of the late endosome is pH 5.2-5.8; this was measured using the intensity ratio of fluorescein. RAB9A is a late endosomal Rab protein that is absolutely required for MPR retrieval. In addition, Press et al. (1998) showed that the late endosome Rab7 was required for proper MPR trafficking. When they expressed inactive Rab7 in cells, the MPR was trapped in an early endosomes and could not return to the TGN . More recent work has also confirmed the role that Rab7 plays in proper retromer localization and function. Thus, the MPR must pass through the late endosome to dissociate lysosomal hydrolases before return to the TGN.