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Cell surface protein aggregation triggers endocytosis to maintain plasma membrane proteostasis.

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Stern, Omer 
Vallis, Yvonne 
Dhillon, Jatinder 
Buchanan, Andrew 


The ability of cells to manage consequences of exogenous proteotoxicity is key to cellular homeostasis. While a plethora of well-characterised machinery aids intracellular proteostasis, mechanisms involved in the response to denaturation of extracellular proteins remain elusive. Here we show that aggregation of protein ectodomains triggers their endocytosis via a macroendocytic route, and subsequent lysosomal degradation. Using ERBB2/HER2-specific antibodies we reveal that their cross-linking ability triggers specific and fast endocytosis of the receptor, independent of clathrin and dynamin. Upon aggregation, canonical clathrin-dependent cargoes are redirected into the aggregation-dependent endocytosis (ADE) pathway. ADE is an actin-driven process, which morphologically resembles macropinocytosis. Physical and chemical stress-induced aggregation of surface proteins also triggers ADE, facilitating their degradation in the lysosome. This study pinpoints aggregation of extracellular domains as a trigger for rapid uptake and lysosomal clearance which besides its proteostatic function has potential implications for the uptake of pathological protein aggregates and antibody-based therapies.



Membrane Proteins, Proteostasis, Cell Membrane, Endocytosis, Antibodies, Clathrin

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Nat Commun

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Springer Science and Business Media LLC
European Molecular Biology Organization (EMBO) (LTF 2015-1380)
RCUK | Medical Research Council (MRC) (U105178795)