Figure 3. Assembly and trafficking of the γ-secretase complex.

The four γ-secretase components (colored as in Fig. (2)) are synthesized in the endoplasmic reticulum (ER), where they await incorporation into stable complexes (bottom right). Unincorporated components are degraded with a half-life (t_1/2) ~ < 6 h; the half-life for components in stable sub-complexes is ~ > 24 h. Rer1p can retrieve unincorporated imNct or Pen-2 that escapes from the ER to the Golgi (center right). The PALP motif of unincorporated PS is exposed (star), such that PS that escapes to the Golgi is rapidly retrieved by an unknown mechanism to return PS to the ER (center right). Shortly after its synthesis, Nct is rapidly N-glycosylated to form the immature, partially-glycosylated form (imNct, bottom right). It is this imNct that binds to Aph-1 in the ER to form a stable 1:1 complex (sub-complex I, bottom left). This stable heterodimer then binds the PS holoprotein (holoPS) in the ER to form the imNct·Aph-1·holoPS heterotrimer (sub-complex II). The mNct·Aph-1·holoPS trimer can now bind Pen-2 to form sub-complex III. PS within this heterotetramer rapidly undergoes endoproteolysis to form N- and C-terminal fragments (PS-NTF and -CTF, respectively), yielding sub-complex IV. Assembly of all four components and the resulting endoproteolysis hides any ER retention signals (e.g. the PALP motif of PS1 and the TMDs of Nct and Pen-2) to allow for exit of the complex from the ER for transit to the Golgi via the ER-Golgi intermediate compartment (ERGIC). These ER retention signals may be buried between the proteins and/or within the membrane. While endoproteolysis may occur in the ER, the ERGIC, and/or the Golgi, endorproteolysis in the ERGIC is represented here. Upon reaching the trans-Golgi, Nct is fully matured to mNct (sub-complex V). It is this complex – PS NTF and CTF, mNct, Aph-1, and Pen-2 – that represents the typical active form of γ-secretase. The majority (~95%) of mature γ-secretase complexes cycles between the ER and the Golgi, with a minority (~5%) that is further trafficked to the plasma membrane or to other membranous components (e.g. endosomes, multivesicular bodies (MVBs), or lysosomes). Once it reaches these compartments, γ-secretase can catalyze the intramembranous cleavage of substrates, such as C99, which is the product of β-secretase cleavage of APP (upper half of figure). Cleavage generates the extracellular/luminal Aβ peptide and the APP intracellular domain (AICD), which can bind to cytosolic effector proteins or translocate to the nucleus to participate in transcriptional regulation. The exact site of Aβ generation is controversial, but several studies have shown γ-secretase activity in the following locations: the cell surface, the endosome, within late endosomes/MVBs, in the lysosome, or in extracellular vesicles after exosome release. For simplicity, glycosylation (orange) was omitted from the upper half of the figure. Please see “Conclusion and Perspective” and Fig. (2) for more details.