Unknown

Dataset Information

0

Par3 and aPKC regulate BACE1 endosome-to-TGN trafficking through PACS1.


ABSTRACT: The cleavage of amyloid precursor protein (APP) by ?-site APP cleaving enzyme 1 (BACE1) is the rate-limiting step in beta amyloid generation during Alzheimer's disease (AD) pathogenesis. In AD brains, BACE1 is abnormally accumulated in endocytic compartments, where the acidic pH is optimal for its activity. However, mechanisms regulating the endosome-to-trans-Golgi network (TGN) retrieval of BACE1 remain unclear. Here, we show that partitioning defective 3 (Par3) facilitates BACE1 retrograde trafficking from endosomes to the TGN. Par3 functions through aPKC-mediated phosphorylation of BACE1 on Ser498, which in turn promotes the interaction between BACE1 and phosphofurin acidic cluster sorting protein 1 and facilitates the retrograde trafficking of BACE1 to the TGN. In human AD brains, there is a significant decrease in Ser498 phosphorylation of BACE1 suggesting that defective phosphorylation-dependent retrograde transport of BACE1 is important in AD pathogenesis. Together, our studies provide mechanistic insight into a novel role for Par3 and aPKC in regulating the retrograde endosome-to-TGN trafficking of BACE1 and shed light on the mechanisms of AD pathogenesis.

SUBMITTER: Sun M 

PROVIDER: S-EPMC5653456 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

altmetric image

Publications

Par3 and aPKC regulate BACE1 endosome-to-TGN trafficking through PACS1.

Sun Miao M   Zhang Huaye H  

Neurobiology of aging 20170921


The cleavage of amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE1) is the rate-limiting step in beta amyloid generation during Alzheimer's disease (AD) pathogenesis. In AD brains, BACE1 is abnormally accumulated in endocytic compartments, where the acidic pH is optimal for its activity. However, mechanisms regulating the endosome-to-trans-Golgi network (TGN) retrieval of BACE1 remain unclear. Here, we show that partitioning defective 3 (Par3) facilitates BACE1 retrograde tra  ...[more]

Similar Datasets

| S-EPMC4420272 | biostudies-literature
| S-EPMC4325844 | biostudies-literature
| S-EPMC7093645 | biostudies-literature
| S-EPMC140234 | biostudies-literature
| S-EPMC4850038 | biostudies-literature
| S-EPMC2516981 | biostudies-literature
| S-EPMC6938271 | biostudies-literature
| S-EPMC5294781 | biostudies-literature
| S-EPMC2887680 | biostudies-literature
| S-EPMC6137026 | biostudies-literature