Abstract
The small GTPase rab5 has been shown to play key roles in the function of both endocytic and phagocytic organelles. Although these organelles share several additional common features, different processes have been proposed to explain their biogenesis. In the present study, we provide evidence that lysosome biogenesis involves mechanisms similar to those previously described for the formation of phagolysosomes. Transient interactions ('kiss and run') between endocytic organelles are shown to occur during lysosome biogenesis. These interactions are regulated initially by the GTPase activity of rab5, as demonstrated by the loss of size-selective fusion between endosomes in cells expressing a GTPase-deficient mutant of rab5. Endocytic compartments in these cells sequentially display properties of early and late endosomes. However, the formation of lysosomes and the sorting of endocytic solute materials to small electron dense vacuoles are not affected by the rab5 mutation. Together, our results indicate that endosome maturation occurs during the early part of lysosome biogenesis. This process involves transient fusion events regulated, in part, by the small GTPase rab5.
Highlights
Endocytosis and lysosome biogenesis are coordinated processes allowing cells to fulfill a variety of functions including internalization of nutrients, the regulation of cellsurface receptor activity, and antigen processing
HRP was present in smaller vacuoles in control cells transfected with the vector only (Fig. 1). This was observed for several transfected clones. These results indicate that transfection of the rab5a(Q79L) cDNA in macrophages has a profound effect on the morphology of endosomes
In control cells at 240 minutes, the size segregation of the two dextran molecules did not appear as extensive as for the 30′/120′ time point, which indicates that some remixing between late endocytic structures could occur, as suggested previously (Luzio et al, 2000). These results indicate that the GTPase activity of rab5 regulates, to some extent, the transient nature (‘kiss and run’) of the fusion events occurring between endosomes in the early part of the process of lysosome biogenesis
Summary
Endocytosis and lysosome biogenesis are coordinated processes allowing cells to fulfill a variety of functions including internalization of nutrients, the regulation of cellsurface receptor activity, and antigen processing (for reviews, see Mellman, 1996; Mukherjee et al, 1997). In the past few years, our understanding of lysosome formation has greatly improved with the identification of several of the molecules involved in membrane interaction and fusion along the endocytic pathway, including SNARE proteins and members of the rab family of small GTP-binding proteins. These proteins are parts of the machinery required for fusion at both early and late stages of the endocytic pathway (Clague, 1999; Mullock et al, 1998). A better comprehension of this aspect of lysosome biogenesis is likely to help us define more clearly its molecular requirements
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