The Intracellular Domain of Sortilin Interacts with Amyloid Precursor Protein and Regulates Its Lysosomal and Lipid Raft Trafficking

Abstract

The processing of Amyloid precursor protein (APP) is multifaceted, comprising of protein transport, internalization and sequential proteolysis. However, the exact mechanism of APP intracellular trafficking and distribution remains unclear. To determine the interaction between sortilin and APP and the effect of sortilin on APP trafficking and processing, we studied the binding site and its function by mapping experiments, colocalization, coimmunoprecipitation and sucrose gradient fractionation. We identified for the first time that sortilin interacts with APP at both N- and C-terminal regions. The sortilin-FLVHRY (residues 787–792) and APP-NPTYKFFE (residues 759–766) motifs are crucial for the C-terminal interaction. We also found that lack of the FLVHRY motif reduces APP lysosomal targeting and increases APP distribution in lipid rafts in co-transfected HEK293 cells. These results are consistent with our in vivo data where sortilin knockout mice showed a decrease of APP lysosomal distribution and an increase of APP in lipid rafts. We further confirmed that overexpression of sortilin-FLVHRY mutants failed to rescue the lysosomal degradation of APP. Thus, our data suggests that sortilin is implicated in APP lysosomal and lipid raft targeting via its carboxyl-terminal F/YXXXXF/Y motif. Our study provides new molecular insights into APP trafficking and processing.

Sortilin mediates vascular calcification via its recruitment into extracellular vesicles

“…The S825 phosphomimetic activated TNAP activity through TGN localization, while the phosphor-null variant localized to lysosomes. These data agree with previous findings that TNAP activation occurs in the early secretory pathway and subsequently moves and localizes to the plasma membrane (26) and that the sortilin intracellular domain controls the fate of interacting partners from the lysosomes to lipid rafts (47). The p825 site enhances the binding of sortilin-to-Golgi-associated, γ-adaptin ear-containing, ARF-binding protein (GGA) -cytosolic adaptors mediating the sorting of transmembrane proteins (48).…”

Amyloid Precursor-like Protein 2 and Sortilin Do Not Regulate the PCSK9 Convertase-mediated Low Density Lipoprotein Receptor Degradation but Interact with Each Other

“…Because the APP motives in its luminal and CT domains implicated in sortilin binding are either identical or similar in APLP2 (not shown), this suggests that sortilin may also bind APLP2 via these motives and regulate its trafficking. Interestingly, sortilin was shown to target APP for lysosomal degradation (55), whereas our data revealed that sortilin stabilizes APLP2 (Fig. 4B), suggesting a functional difference between the interaction of sortilin with APP or APLP2.…”

“…It was shown that sortilin and the amyloid precursor protein (APP) bind to each other via luminal (head-to-head) and cytosolic (tail-to-tail) interaction domains (55). Their cytosolic tails interact via the FLVHRY motif of sortilin with the YNPTYKFFE motif in APP, which overlaps with the ARH binding consensus YENPTY (26,27).…”

Amyloid beta1–42 (Aβ42) up‐regulates the expression of sortilin via the p75NTR/RhoA signaling pathway

“…) and negatively regulates APP lipid raft targeting (Yang et al . ). Furthermore, sortilin interacts with p75 NTR to induce neuronal apoptosis and increase AD severity (Skeldal et al .…”