The Rab5 activator RME-6 is required for amyloid precursor protein endocytosis depending on the YTSI motif.

ABSTRACT: Endocytosis of the amyloid precursor protein (APP) is critical for generation of ?-amyloid, aggregating in Alzheimer's disease. APP endocytosis depending on the intracellular NPTY motif is well investigated, whereas involvement of the YTSI (also termed BaSS) motif remains controversial. Here, we show that APP lacking the YTSI motif (?YTSI) displays reduced localization to early endosomes and decreased internalization rates, similar to APP ?NPTY. Additionally, we show that the YTSI-binding protein, PAT1a interacts with the Rab5 activator RME-6, as shown by several independent assays. Interestingly, knockdown of RME-6 decreased APP endocytosis, whereas overexpression increased the same. Similarly, APP ?NPTY endocytosis was affected by PAT1a and RME-6 overexpression, whereas APP ?YTSI internalization remained unchanged. Moreover, we could show that RME-6 mediated increase of APP endocytosis can be diminished upon knocking down PAT1a. Together, our data identify RME-6 as a novel player in APP endocytosis, involving the YTSI-binding protein PAT1a.

SUBMITTER: Eggert S 

PROVIDER: S-EPMC7671991 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature