Activity-regulated trafficking of the palmitoyl-acyl transferase DHHC5

Nat Commun. 2015 Sep 3;6:8200. doi: 10.1038/ncomms9200.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyltransferases / metabolism*
  • Animals
  • Blotting, Western
  • Catenins / metabolism*
  • Dendrites / metabolism
  • Disks Large Homolog 4 Protein
  • Endocytosis
  • HEK293 Cells
  • Hippocampus / cytology
  • Humans
  • Image Processing, Computer-Assisted
  • Immunohistochemistry
  • Immunoprecipitation
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lipoylation
  • Membrane Proteins / metabolism*
  • Microscopy, Confocal
  • Neuronal Plasticity
  • Neurons / metabolism*
  • Neurons / ultrastructure
  • Optical Imaging
  • Phosphorylation
  • Photobleaching
  • Protein Transport
  • Proto-Oncogene Proteins c-fyn / metabolism*
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Catenins
  • Disks Large Homolog 4 Protein
  • Dlg4 protein, rat
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • delta catenin
  • Acyltransferases
  • Zdhhc5 protein, rat
  • Proto-Oncogene Proteins c-fyn