Activity-regulated trafficking of the palmitoyl-acyl transferase DHHC5.
Synaptic plasticity is mediated by the dynamic localization of proteins to and from synapses. This is controlled, in part, through activity-induced palmitoylation of synaptic proteins. Here we report that the ability of the palmitoyl-acyl transferase, DHHC5, to palmitoylate substrates in an activity-dependent manner is dependent on changes in its subcellular localization. Under basal conditions, DHHC5 is bound to PSD-95 and Fyn kinase, and is stabilized at the synaptic membrane through Fyn-mediated phosphorylation of a tyrosine residue within the endocytic motif of DHHC5. In contrast, DHHC5's substrate, δ-catenin, is highly localized to dendritic shafts, resulting in the segregation of the enzyme/substrate pair. Neuronal activity disrupts DHHC5/PSD-95/Fyn kinase complexes, enhancing DHHC5 endocytosis, its translocation to dendritic shafts and its association with δ-catenin. Following DHHC5-mediated palmitoylation of δ-catenin, DHHC5 and δ-catenin are trafficked together back into spines where δ-catenin increases cadherin stabilization and recruitment of AMPA receptors to the synaptic membrane.
Department of Cellular and Physiological Sciences, and the Djavad Mowafaghian Center for Brain Health, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, Canada, V6T-1Z3.
G Stefano
GS
Brigidi
Department of Cellular and Physiological Sciences, and the Djavad Mowafaghian Center for Brain Health, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, Canada, V6T-1Z3.
Brendan
B
Santyr
Department of Cellular and Physiological Sciences, and the Djavad Mowafaghian Center for Brain Health, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, Canada, V6T-1Z3.
Jordan
J
Shimell
Department of Cellular and Physiological Sciences, and the Djavad Mowafaghian Center for Brain Health, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, Canada, V6T-1Z3.
Blair
B
Jovellar
Department of Cellular and Physiological Sciences, and the Djavad Mowafaghian Center for Brain Health, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, Canada, V6T-1Z3.
Shernaz X
SX
Bamji
D000217:Acyltransferases / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D051177:Catenins / Q000378:metabolism*; D003712:Dendrites / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D004705:Endocytosis; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D054878:Lipoylation; D008565:Membrane Proteins / Q000378:metabolism*; D018613:Microscopy, Confocal; D009473:Neuronal Plasticity; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D061848:Optical Imaging; D010766:Phosphorylation; D038761:Photobleaching; D021381:Protein Transport; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000095002:Delta Catenin
D051177:Catenins; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D000217:Acyltransferases; C000606832:Zdhhc5 protein, rat; D051076:Proto-Oncogene Proteins c-fyn; D000095002:Delta Catenin