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Title: Sequence-dependent internalisation of aggregating peptides
Authors: Couceiro, Jose R
Gallardo, Rodrigo
De Smet, Frederik
De Baets, Greet
Baatsen, Pieter
Annaert, Wim
Roose, Kenny
Saelens, Xavier
Schymkowitz, Joost #
Rousseau, Frederic # ×
Issue Date: 2-Jan-2015
Publisher: American Society for Biochemistry and Molecular Biology
Series Title: Journal of Biological Chemistry vol:290 issue:1 pages:242-58
Article number: 10.1074/jbc.M114.586636
Abstract: Recently a number of aggregation disease polypeptides have been shown to spread from cell to cell thereby displaying prionoid behaviour. Studying aggregate internalisation however is often hampered by the complex kinetics of the aggregation process resulting in the concomitant uptake of aggregates of different sizes by competing mechanisms, which makes it difficult to isolate pathway-specific responses to aggregates. We designed synthetic aggregating peptides bearing different aggregation propensities with the aim of producing modes of uptake that are sufficiently distinct to differentially analyse the cellular response to internalization. We found that small acidic aggregates (≤500 nm diameter) were taken up by non-specific endocytosis as part of the fluid phase and travelled through the endosomal compartment to lysosomes. By contrast, basic bigger aggregates (>1 μm) were taken up through a mechanism dependent of cytoskeletal reorganization and membrane remodelling with the morphological hallmarks of phagocytosis. Importantly, the properties of these aggregates not only determined the mechanism of internalization but also the involvement of the proteostatic machinery (the assembly of interconnected networks that control the biogenesis, folding, trafficking and degradation of proteins) in the process: while the internalization of small acidic aggregates is HSF1 independent, the uptake of larger basic aggregates was HSF1 dependent requiring Hsp70. Our results show that the biophysical properties of aggregates determine both their mechanism of internalisation and proteostatic response. It remains to be seen whether these differences in cellular response contribute to the particular role of specific aggregated proteins in disease.
URI: 
ISSN: 0021-9258
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Switch Laboratory
Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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