FIGURE 10:

Proposed model for endosomal trafficking of BACE1 phosphomutants. After internalization, BACE1 is transported from the early endosomes to the recycling endosomes. Nonphosphorylated BACE1 is transported to the recycling endosomes at a slower rate than phosphorylated BACE1, leading to an extended residency time of nonphosphorylated BACE1 in early endosomes. We propose that nonphosphorylated BACE1 utilizes the SNX4 signal-independent transport pathway to the recycling endosomes, whereas phosphory­lated BACE1 is transported by a retromer/GGA1-dependent fast pathway. On retromer/GGA1 depletion, the phosphorylated BACE1 is transported at the same rate as the nonphosphorylated species, and we propose that in the absence of either retromer or GGA1 the phosphorylated and nonphosphorylated species use the same SNX4 pathway to the recycling endosome. Phosphorylated BACE1 is unaffected by the depletion of SNX4.