Abstract
ABSTRACTRab5 and Rab7a are the main determinants of early and late endosomes and are important regulators of endosomal progression. The transport from early endosomes to late endosome seems to be regulated through an endosomal maturation switch, where Rab5 is gradually exchanged by Rab7a on the same endosome. Here, we provide new insight into the mechanism of endosomal maturation, for which we have discovered a stepwise Rab5 detachment, sequentially regulated by Rab7a. The initial detachment of Rab5 is Rab7a independent and demonstrates a diffusion-like first-phase exchange between the cytosol and the endosomal membrane, and a second phase, in which Rab5 converges into specific domains that detach as a Rab5 indigenous endosome. Consequently, we show that early endosomal maturation regulated through the Rab5-to-Rab7a switch induces the formation of new fully functional Rab5-positive early endosomes. Progression through stepwise early endosomal maturation regulates the direction of transport and, concomitantly, the homeostasis of early endosomes.
Highlights
Endosomal trafficking is carefully regulated through the mechanisms of endosomal progression
Detachment of Rab5 occurs in two phases Endosomal progression, from early to late endosomes, is carefully regulated by the transition from a Rab5-positive to a Rab7a-positive endosome
When comparing the D1/2 values between the three experiments, we found a significant difference in the D1/2 for mCh-Rab5 when the cells were co-transfected with Rab7a or Rab7aQ67L (Fig. 1D)
Summary
Endosomal trafficking is carefully regulated through the mechanisms of endosomal progression. The shuttling model is based on preexisting early endosomes that function as a stationary recycling compartment. From this compartment, carrier vesicles are released to recycle back to the plasma membrane or to interact and fuse with late endosomes (Griffiths and Gruenberg, 1991). The maturation model emphasizes the function of the early endosome as a transient compartment, where transport between early to late endosomes is driven by endosomal maturation. With this model, the early endosomes are constantly regenerated through endosomal maturation and are not stationary compartments (Murphy, 1991).
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