The adhesion molecule CHL1 regulates uncoating of clathrin-coated synaptic vesicles.
In searching for binding partners of the intracellular domain of the immunoglobulin superfamily adhesion molecule CHL1, we identified the clathrin-uncoating ATPase Hsc70. CHL1 gene ablation resulted in reduced targeting of Hsc70 to the synaptic plasma membrane and synaptic vesicles, suggesting CHL1 as a synapse-targeting cue for Hsc70. CHL1 accumulates in presynaptic membranes and, in response to synapse activation, is targeted to synaptic vesicles by endocytosis. CHL1 deficiency or disruption of the CHL1/Hsc70 complex results in accumulation of abnormally high levels of clathrin-coated synaptic vesicles with a reduced ability to release clathrin. Generation of new clathrin-coated synaptic vesicles in an activity-dependent manner is inhibited when the CHL1/Hsc70 complex is disrupted, resulting in impaired uptake and release of FM dyes in synaptic boutons. Abnormalities in clathrin-dependent synaptic vesicle recycling may thus underlie brain malfunctions in humans and mice that carry mutations in the CHL1 gene.
Leshchyns'ka
Iryna
I
Zentrum für Molekulare Neurobiologie, Universität Hamburg, Martinistrasse 52, 20246 Hamburg, Germany.
Sytnyk
Vladimir
V
Richter
Melanie
M
Andreyeva
Aksana
A
Puchkov
Dmytro
D
Schachner
Melitta
M
D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000187:drug effects; D015153:Blotting, Western / Q000379:methods; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000172:deficiency / Q000276:immunology / Q000502:physiology*; D002478:Cells, Cultured; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D015180:Electrophoresis, Gel, Two-Dimensional / Q000379:methods; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D005455:Fluorescent Antibody Technique / Q000379:methods; D015870:Gene Expression / Q000502:physiology; D050883:HSC70 Heat-Shock Proteins / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology*; D010088:Oxidoreductases / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D016708:Synaptophysin / Q000378:metabolism; D013997:Time Factors; D014162:Transfection / Q000379:methods
D000906:Antibodies; D002135:Calcium-Binding Proteins; D015815:Cell Adhesion Molecules; C490649:Chl1 protein, mouse; D002868:Chromosomal Proteins, Non-Histone; D050883:HSC70 Heat-Shock Proteins; C488911:Hpd protein, mouse; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C489614:Sv2a protein, mouse; D016708:Synaptophysin; C056608:caltractin; D010088:Oxidoreductases; D011188:Potassium