Calpain hydrolysis of alpha- and beta2-adaptins decreases clathrin-dependent endocytosis and may promote neurodegeneration.
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 alpha- and beta2-subunits of the tetrameric adaptor protein complex 2 by calpain. Calcium-dependent alpha- and beta2-adaptin hydrolysis was observed in several rat tissues, including brain and primary neuronal cultures. Neuronal alpha- and beta2-adaptin cleavage was inducible by glutamate stimulation and was accompanied by the decreased endocytosis of transferrin. Heterologous expression of truncated forms of the beta2-adaptin subunit significantly decreased the membrane recruitment of clathrin and inhibited clathrin-mediated receptor endocytosis. Moreover, the presence of truncated beta2-adaptin sensitized neurons to glutamate receptor-mediated excitotoxicity. Proteolysis of alpha- and beta2-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.
Rudinskiy
Nikita
N
Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Station 15, Lausanne CH1015, Switzerland.
Grishchuk
Yulia
Y
Vaslin
Anne
A
Puyal
Julien
J
Delacourte
André
A
Hirling
Harald
H
Clarke
Peter G H
PG
Luthi-Carter
Ruth
R
D033965:Adaptor Protein Complex alpha Subunits / Q000235:genetics / Q000378:metabolism*; D033966:Adaptor Protein Complex beta Subunits / Q000235:genetics / Q000378:metabolism*; D033942:Adaptor Proteins, Vesicular Transport; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002966:Clathrin / Q000235:genetics / Q000378:metabolism*; D004705:Endocytosis; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D008297:Male; D008563:Membrane Lipids / Q000235:genetics / Q000378:metabolism; D034041:Monomeric Clathrin Assembly Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar
D033965:Adaptor Protein Complex alpha Subunits; D033966:Adaptor Protein Complex beta Subunits; D033942:Adaptor Proteins, Vesicular Transport; D002966:Clathrin; D008563:Membrane Lipids; D034041:Monomeric Clathrin Assembly Proteins; C439003:PICALM protein, human; C499980:Picalm protein, rat; C114154:epsin; D018698:Glutamic Acid; D002154:Calpain; D002118:Calcium