Fig. 5. Percolation-model that integrates -secretase assembly into ER-Golgi transport regulation. Individual and newly synthetised -secretase components are co-translationally inserted in the ER. Given that NCT interacts very early with APH1 and that Rer1p preferentially binds to immature NCT, we suggest that immature NCT `percolates' between the ER and Golgi compartments (a). It can be captured by Rer1p in the IC (a') or cis-Golgi (a'') and retrieved via COPI-coated organelles to the ER. By competing with the NCT TMD, APH1 can displace Rer1p to form an NCT-APH1 subcomplex. This can occur in the ER (b) as well as IC compartments (b'). Once NCT-APH1 is formed, PS1 and PEN2 (either sequentially or together, see Fig. 4) join it to form a fully assembled complex. Again, this event does not need to be restricted to the ER (c) but can also take place in the IC (c'). Full-length PS1 can exit the ER (Kim et al., 2005), which suggests that endoproteolysis (and PEN2 interaction) occurs later and maybe during additional retrieval events from Golgi/IC to ER. The concentration of endogenous PS1 in COPI-coated membranes (Rechards et al., 2003) indicates that PS1 percolates through early biosynthetic compartments but potential retrieval mechanisms have not yet been identified. Hence, the ER-Golgi quality control system ensures that monomeric -secretase components are selectively retrieved from the cis-Golgi to the ER through interaction with cargo-retrieval receptors. Conversely, full complex assembly leads to a masking of the interactions with these retrieval receptors, allowing escape from ER-Golgi recycling (d) and transport of assembled complexes to their final destination in distal compartments, including the cell surface and endosomes. APP behaves differently because it has a short residence time in ER-Golgi compartments and gets maturely glycosylated quickly. This supports the finding that APP trafficking from the ER is uncoupled from PS1 (Kim et al., 2005) (e).