Intracellular Cycling of Lysosomal Enzyme Receptors: Cytoplasmic Tails' Tales

Despite impressive progress in identifying factors that influence lysosomal enzyme receptor distribution, constructing a unified trafficking model is complicated. Trafficking occurs through a dynamic system of organelles connected by multiple transport pathways, making it difficult to assign a particular localization defect to a specific transport step. Compositional differences between organelles can be vague, especially in mutant cells, hindering compartment identification. For these, and other reasons, an integrated understanding of MPR and Vps10p sorting has yet to be achieved. Hypothetical models are depicted in Figure 2Figure 2.Figure 2Hypothetical Models for Intracellular Trafficking of Lysosomal Enzyme Sorting ReceptorsThick lines represent possible active sorting steps; numbers denote alternative destinations for some of the transport events. Thin lines represent minor, possibly default, transport steps not discussed in the text.(A) MPR sorting in mammalian cells. MPRs are distributed primarily in organelles colored yellow. Early endosomes are generally located in the cell periphery, late endosomes and TGN in a more perinuclear distribution. Transport between early and late endosomes could occur by a carrier-mediated process or by maturation of early into late endosomes.(B) Vps10p sorting in yeast cells. Unlike MPR, Vps10p does not seem to traffic through the plasma membrane. The AP-1-dependent pathway may not require sorting signal recognition. The extent of Vps10p trafficking through early endosomes is unknownView Large Image | View Hi-Res Image | Download PowerPoint SlideAlthough mammalian GGA proteins likely function with clathrin in MPR sorting at the TGN (Figure 2A(Figure 2A), it remains to be ascertained whether GGA function is independent of AP complexes. Could AP-1 still participate in MPR sorting at the TGN, either together with GGAs in the same transport carriers or in a distinct pathway? AP-1-deficient mouse cells displayed severely reduced association of clathrin with the TGN at steady state, raising the possibility that AP-1 might be key for clathrin coat assembly at this organelle (Meyer et al., 2000xMeyer, C., Zizioli, D., Lausmann, S., Eskelinen, E.-L., Hamann, J., Saftig, P., von Figura, K., and Schu, P. EMBO J. 2000; 19: 2193–2203Crossref | PubMedSee all References(Meyer et al., 2000). However, formation of transient clathrin-coated carriers, with or without GGAs, was not addressed. Another open question is the precise destination of GGA-mediated MPR transport. If MPRs are preferentially transported to early (Figure 2AFigure 2A, arrow 1) rather than late (Figure 2AFigure 2A, arrow 2) endosomes, sorting at early endosomes would be especially important. On the other hand, analysis of yeast GGA mutants led Black and Pelham (2000)xBlack, M.W. and Pelham, H.R.B. J. Cell Biol. 2000; 151: 587–600Crossref | PubMed | Scopus (110)See all ReferencesBlack and Pelham (2000) to propose that Gga proteins mediate direct transport from TGN to prevacuolar/late endosomes and AP-1 from TGN to early endosomes (Figure 2B(Figure 2B), a hypothesis not yet directly tested in either yeast or mammalian cells.MPR retrieval from endosomes is even more complicated. What are the relative contributions of PACS-1 and TIP47? The phenotypes resulting from interfering with PACS-1 (MPR accumulation in peripheral endosomes) are distinct from those caused by interfering with TIP47 (MPR degradation in lysosomes), making it improbable that PACS-1 and TIP47 act together, or in distinct pathways from the same compartment. Instead, the data are more compatible with PACS-1/AP-1 function earlier in the endocytic pathway than TIP47/Rab9. In this context, there are several possible relationships between PACS-1 and TIP47 retrieval pathways, in part depending on the destination of GGA-mediated transport. For example, PACS-1 sorting of MPRs from early endocytic compartments to the TGN (Figure 2AFigure 2A, arrow 3) could represent the major retrieval pathway and TIP47 could act in a last-chance salvage pathway before delivery to lysosomes. Alternatively, the major retrieval pathway for MPR could involve TIP47-mediated transport from late endosomes while a minor PACS-1 pathway could direct MPR retrieval from earlier endosomal compartments, either directly to the TGN or to late endosomes where the TIP47 pathway would take over (Figure 2AFigure 2A, arrows 3 and 4). Lastly, an obligatorily sequential pathway is possible where PACS-1 directs MPR to late endosomes (Figure 2AFigure 2A, arrow 4) for TIP47-mediated return to the TGN.Where does the retromer complex fit in? Strong evidence in yeast places the retromer in retrieval from prevacuolar/late endosomes (Figure 2B(Figure 2B). A similar site of action in mammalian cells would raise the possibility that retromer functions together with TIP47. In this scenario, TIP47 would serve to collect MPR into retromer-coated transport carriers. The mammalian homolog of Vps35p could also participate in decoding sorting information of MPRs or other cargo (sortilin?).Finally, how is sorting signal recognition regulated so that interaction with each tail binding protein occurs only at the appropriate organelle? Phosphorylation and palmitoylation of MPR receptor tails have been invoked as mechanisms to control tail recognition (Le Borgne and Hoflack, 1998xLe Borgne, R. and Hoflack, B. Biochim. Biophys. Acta. 1998; 1404: 195–209Crossref | PubMed | Scopus (108)See all References(Le Borgne and Hoflack, 1998). Cooperative association of cargo, tail binding proteins, and additional factors into multimeric, organelle-specific complexes is another attractive hypothesis recently put forth for PACS-1/AP-1 and for TIP47/Rab9 (Carroll et al. 2001xCarroll, K.S., Hanna, J., Simon, I., Krise, J., Barbero, P., and Pfeffer, S.R. Science. 2001; 292: 1373–1376Crossref | PubMed | Scopus (170)See all References, Crump et al. 2001xCrump, C.M., Xiang, Y., Thomas, L., Gu, F., Austin, C., Tooze, S.A., and Thomas, G. EMBO J. 2001; 20: 2191–2201Crossref | PubMed | Scopus (130)See all References).In conclusion, the recent findings present a maze of possibilities for trafficking of lysosomal enzyme receptors. Solving this maze will require a new level of experimental integration, combining perturbations of multiple sorting factors with high-resolution kinetic measurements of individual transport events.