Cell surface protein aggregation triggers endocytosis to maintain plasma membrane proteostasis

David Paul, Omer Stern, Yvonne Vallis, Jatinder Dhillon, Andrew Buchanan and Harvey McMahon ()
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David Paul: Francis Crick Avenue
Omer Stern: Francis Crick Avenue
Yvonne Vallis: Francis Crick Avenue
Jatinder Dhillon: Antibody Discovery & Protein Engineering, Granta Park
Andrew Buchanan: Antibody Discovery & Protein Engineering, Granta Park
Harvey McMahon: Francis Crick Avenue

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-36496-y

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