The intracellular trafficking of BACE1. (1) Following synthesis in the ER, pro-BACE1 traffics to the Golgi. Here, the propeptide is removed and BACE1 undergoes significant post-translational modifications. The trafficking and localization of BACE1 appear dependent on the ACDL motif, composed of DISLL residues, in its C-terminal tail. Importantly, phosphorylation of the serine 498 residue (S498) is important for binding of BACE1 to the GGA monomeric adaptor proteins which are implicated in the sorting of cargo between the TGN and endosomes and vice versa [127-131], in addition to the Golgi complex to the endosomes . (2) BACE1 traffics to the plasma membrane and while the re-internalization of BACE1 from the cell surface appears to be independent of the phosphorylation state of S498 , it has been reported that the di-leucine residues are important for BACE1 endocytosis . Non-phosphorylated BACE1 may recycle from the endosome back to the cell surface . However, BACE1 phosphorylated at the S498 site interacts with GGA1 in the endosome and traffics back to the TGN , and (3) the interaction of phosphorylated BACE1 with GGA3 appears to direct BACE1 to the lysosome, where it is degraded . In addition to S498 phosphorylation, the di-leucine residues are also important for the sorting of BACE1 into lysosomal compartments . BACE1 is also degraded in the proteasome . The precise subcellular localization (early verses late endosomes) of the BACE1-GGA complex requires determination, and while it appears likely that BACE1 can traffic from the TGN to the endosome directly, it remains to be demonstrated experimentally.