Abstract
Protein interacting with Amyloid Precursor Protein (APP) tail 1 (PAT1) also called APPBP2 or Ara 67 has different targets such as APP or androgen receptor and is expressed in several tissues. PAT1 is known to be involved in the subcellular trafficking of its targets. We previously observed in primary neurons that PAT1 is poorly associated with APP at the cell surface. Here we show that PAT1 colocalizes with vesicles close to the cell surface labeled with Rab5, Rab4, EEA1 and Rabaptin-5 but not with Rab11 and Rab7. Moreover, PAT1 expression regulates the number of EEA1 and Rab5 vesicles, and endocytosis/recycling of the transferrin receptor. In addition, low levels of PAT1 decrease the size of transferrin-colocalized EEA1 vesicles with time following transferrin uptake. Finally, overexpression of the APP binding domain to PAT1 is sufficient to compromise endocytosis. Altogether, these data suggest that PAT1 is a new actor in transferrin early endocytosis. Whether this new function of PAT1 may have consequences in pathology remains to be determined.
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Acknowledgements
We thank Dr. Sanjay W. Pimplikar for mab26 to PAT1 and Dr. Marino Zerial for Rabaptin-5 antibody and Dr. Christophe Lamaze for helpful discussions. This work was supported by Institut National de la Santé et de la Recherche Médicale, France and by Fondation Jérôme Lejeune, France.
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Fig. 1S PAT1 is also involved in mature neurons at 15 DIV. (a) Neurons at 15DIV were immunolabeled for PAT1 and EEA1 and for PAT1 and Rab5. Representative image is presented for both double immunolabelings. Enlarged inset is presented on the right. Scale bar: 10 µm; Scale bar of enlarged inset:5 µm. Pearson’s coefficient for soma and dendrites is presented for PAT1/EEA1 (30 cells analyzed) and for PAT1/Rab5 (30 cells analyzed). (b) Number of EEA1 vesicles per cell surface (µm2) are presented for soma and dendrites both in PAT1 siRNAs conditions and in control (Ctrl) in the absence of treatment (30 cells analyzed per condition). (c) Transferrin (Tf) uptake at 30 min in PAT1 siRNAs conditions and in control(Ctrl) in the absence of treatment is expressed in integrated density/cell (30 cells analyzed per condition). *p < 0.05; ***p < 0.001 (JPEG 1074 kb)
18_2019_3157_MOESM2_ESM.tif
Fig. 2S Colocalization of Transferrin uptake in EEA1 vesicles with time. (a) Mean volume of EEA1 vesicles in PAT1 siRNAs and Control (Ctrl) in the absence of treatment (50 cells analyzed in each condition). (b) Number of colocalized Transferrin/EEA1 vesicles in PAT1 siRNAs and Control (Ctrl) in the absence of treatment. Quantification is presented in vesicle number per cell volume (µm3) at different time points of transferrin uptake (30 cells analyzed in each condition). (c) Size of colocalizing EEA1/Transferrin with time. Representative images of EEA1/Transferrin are presented at 5, 10, 20 min after transferrin uptake in PAT1siRNAs and Control (Ctrl) conditions. Scale bar: 10 µm; Scale bar of enlarged inset:5 µm. Quantification of colocalized EEA1/Transferrin vesicle size at 10 and 20 min for PAT1 siRNAs and control (Ctrl) is expressed in % (30 cells per condition). *p < 0.05; **p < 0.001 (TIFF 4311 kb)
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Dilsizoglu Senol, A., Tagliafierro, L., Gorisse-Hussonnois, L. et al. Protein interacting with Amyloid Precursor Protein tail-1 (PAT1) is involved in early endocytosis. Cell. Mol. Life Sci. 76, 4995–5009 (2019). https://doi.org/10.1007/s00018-019-03157-7
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DOI: https://doi.org/10.1007/s00018-019-03157-7