Protein interacting with Amyloid Precursor Protein tail-1 (PAT1) is involved in early endocytosis

Senol, Aysegul Dilsizoglu; Tagliafierro, Lidia; Gorisse-Hussonnois, Lucie; Rebeillard, Florian; Huguet, Léa; Geny, David; Contremoulins, Vincent; Corlier, Fabian; Potier, Marie‐Claude; Chasseigneaux, Stéphanie; Darmon, Michèle; Allinquant, Bernadette

doi:10.1007/s00018-019-03157-7

Cited by 9 publications

(13 citation statements)

References 49 publications

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“…As shown in Figure 2A,B, the presence of Pitstop2 or dynasore did not significantly change the basal protein level of APP; and in cells treated with Pitstop2 or dynasore, the reduction of APP protein level by AP2S1 siRNA remained significant. EEA1 is a marker of early endosomes that receive endocytotic materials from cell surface 33,34 . We also found that the colocalization of APP with EEA1 was not altered by AP2S1 KD (Figure 2C), suggesting that endocytosis of APP was less likely involved in AP2S1‐mediated regulation of APP protein.…”

Section: Resultsmentioning

confidence: 74%

AP2S1 regulates APP degradation through late endosome–lysosome fusion in cells and APP/PS1 mice

Wen

Luo

Xie

et al. 2022

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AP2S1 is the sigma 2 subunit of adaptor protein 2 (AP2) that is essential for endocytosis. In this study, we investigated the potential role of AP2S1 in intracellular processing of amyloid precursor protein (APP), which contributes to the pathogenesis of Alzheimer disease (AD) by generating the toxic β-amyloid peptide (Aβ). We found that knockdown or overexpression of AP2S1 decreased or increased the protein levels of APP and Aβ in cells stably expressing human full-length APP695, respectively. This effect was unrelated to endocytosis but involved lysosomal degradation.Morphological studies revealed that silencing of AP2S1 promoted the translocalization of APP from RAB9-positive late endosomes (LE) to LAMP1-positive lysosomes, which was paralleled by the enhanced LE-lysosome fusion. In support, silencing of vacuolar protein sorting-associated protein 41 (VPS41) that is implicated in LE-lyso fusion prevented AP2S1-mediated regulation of APP degradation and translocalization. In APP/PS1 mice, an animal model of AD, AAV-mediated delivery of AP2S1 shRNA in the hippocampus significantly reduced the protein levels of APP and Aβ, with the concomitant APP translocalization, LE-lyso fusion and the improved cognitive functions. Taken together, these data uncover a LE-lyso fusion mechanism in APP degradation and suggest a novel role for AP2S1 in the pathophysiology of AD.

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Section: Resultsmentioning

confidence: 74%

AP2S1 regulates APP degradation through late endosome–lysosome fusion in cells and APP/PS1 mice

Wen

Luo

Xie

et al. 2022

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“…After endocytosed vesicles enter the cell, Rab GTPases are rapidly recruited by effector proteins, which mediate the formation of early endosomes. During this process, Rabep1 interacts with Rab5, thus leading to an increase in the uptake of endocytic substances [ 31 ]. Yi Wang et al also found that Rabep1, as a key effector molecule of Rab5, can affect the efficiency of cell endocytosis by regulating the early endosome fusion mediated by Rab5 [ 32 ].…”

Section: Resultsmentioning

confidence: 99%

The Rabep1-Mediated Endocytosis and Activation of Trypsinogen to Promote Pancreatic Stellate Cell Activation

Yao

Luo

et al. 2022

Biomolecules

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Background: The pathogenesis of chronic pancreatitis is still unclear. Trypsinogen activation is an active factor in acute pancreatitis that has not been studied in the occurrence of chronic pancreatitis. Methods: Immunofluorescence was used to detect the location and expression of trypsinogen in chronic pancreatitis and normal tissues. Microarray and single-cell RNA-seq (scRNA-seq) were used to screen core genes and pathways in pancreatic stellate cells (PSCs). Western blotting and immunofluorescence were used to verify trypsinogen expression in PSCs after silencing Rabep1. Immunofluorescence and flow cytometry were used to validate trypsinogen activation and PSC activation after intervening in the endocytosis pathway. Results: Endocytosed trypsinogen was found in PSCs in CP clinical samples. Bioinformatic analysis showed that Rabep1 is a core gene that regulates trypsinogen endocytosis through the endocytosis pathway, verified by Western blot and immunofluorescence. Immunofluorescence and flow cytometry analyses confirmed the activation of trypsinogen and PSCs through the endocytosis pathway in PSCs. Conclusion: This study discovered a new mechanism by which trypsinogen affects the activation of PSCs and the occurrence and development of CP. Through communication between pancreatic acinar cells and PSCs, trypsinogen can be endocytosed by PSCs and activated by the Rabep1 gene.

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“…For this purpose, additional secondary antibodies, mouse Alexa Fluor 594 (to detect internalized APP), and either rabbit Alexa Fluor 647 or rat Alexa Fluor 647 (to visualize Flag RME-6 or PAT1a HA) were added, respectively. The fourth alternative of this assay involving overexpression of RME-6 included knockdown of PAT1a with an siRNA (Dharmacon) (ID numbers: J-059477-10 and J-059477-12) [38], 48 h prior to the start of the experiment.…”

Section: Antibody Uptake Assaymentioning

confidence: 99%

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

Eggert

Gruebl

Rajender

et al. 2020

Cell. Mol. Life Sci.

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Endocytosis of the amyloid precursor protein (APP) is critical for generation of β-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 (ΔYTSI) displays reduced localization to early endosomes and decreased internalization rates, similar to APP ΔNPTY. 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 ΔNPTY endocytosis was affected by PAT1a and RME-6 overexpression, whereas APP ΔYTSI 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.

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Protein interacting with Amyloid Precursor Protein tail-1 (PAT1) is involved in early endocytosis

Cited by 9 publications

References 49 publications

AP2S1 regulates APP degradation through late endosome–lysosome fusion in cells and APP/PS1 mice

AP2S1 regulates APP degradation through late endosome–lysosome fusion in cells and APP/PS1 mice

The Rabep1-Mediated Endocytosis and Activation of Trypsinogen to Promote Pancreatic Stellate Cell Activation

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

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