Calpain hydrolysis of α- and β2-adaptins decreases clathrin-dependent endocytosis and may promote neurodegeneration

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Abstract

Clathrin-dependent endocytosis is mediated by a tightly regulated network of molecular interactions that provides essential protein-protein and protein-lipid binding activities. Here we report the hydrolysis of the α- and β2-subunits of the tetrameric adaptor protein complex 2 by calpain. Calcium-dependent α- and β2-adaptin hydrolysis was observed in several rat tissues, including brain and primary neuronal cultures. Neuronal α- and β2-adaptin cleavage was inducible by glutamate stimulation and was accompanied by the decreased endocytosis of transferrin. Heterologous expression of truncated forms of the β2-adaptin subunit significantly decreased the membrane recruitment of clathrin and inhibited clathrin-mediated receptor endocytosis. Moreover, the presence of truncated β2-adaptin sensitized neurons to glutamate receptor-mediated excitotoxicity. Proteolysis of α- and β2-adaptins, as well as the accessory clathrin adaptors epsin 1, adaptor protein 180, and the clathrin assembly lymphoid myeloid leukemia protein, was detected in brain tissues after experimentally induced ischemia and in cases of human Alzheimer disease. The present study further clarifies the central role of calpain in regulating clathrin-dependent endocytosis and provides evidence for a novel mechanism through which calpain activation may promote neurodegeneration: the sensitization of cells to glutamate-mediated excitotoxicity via the decreased internalization of surface receptors. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.

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Rudinskiy, N., Grishchuk, Y., Vaslin, A., Puyal, J., Delacourte, A., Hirling, H., … Luthi-Carter, R. (2009). Calpain hydrolysis of α- and β2-adaptins decreases clathrin-dependent endocytosis and may promote neurodegeneration. Journal of Biological Chemistry, 284(18), 12447–12458. https://doi.org/10.1074/jbc.M804740200

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