Degradation of postsynaptic scaffold GKAP and regulation of dendritic spine morphology by the TRIM3 ubiquitin ligase in rat hippocampal neurons.
Changes in neuronal activity modify the structure of dendritic spines and alter the function and protein composition of synapses. Regulated degradation of postsynaptic density (PSD) proteins by the ubiquitin-proteasome system is believed to play an important role in activity-dependent synaptic remodeling. Stimulating neuronal activity in vitro and in vivo induces the ubiquitination and degradation of GKAP/SAPAP and Shank, major scaffold proteins of the PSD. However, the specific ubiquitin ligases that regulate postsynaptic protein composition have not been identified. Here we identify the RING finger-containing protein TRIM3 as a specific E3 ubiquitin ligase for the PSD scaffold GKAP/SAPAP1. Present in PSD fractions from rat brain, TRIM3 stimulates ubiquitination and proteasome-dependent degradation of GKAP, and induces the loss of GKAP and associated scaffold Shank1 from postsynaptic sites. Suppression of endogenous TRIM3 by RNA interference (RNAi) results in increased accumulation of GKAP and Shank1 at synapses, as well as enlargement of dendritic spine heads. RNAi of TRIM3 also prevented the loss of GKAP induced by synaptic activity. Thus, TRIM3 is a novel E3 ligase that mediates activity-dependent turnover of PSD scaffold proteins and is a negative regulator of dendritic spine morphology.
Hung
Albert Y
AY
Departments of Brain and Cognitive Sciences and Biology, The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
Sung
Clifford C
CC
Brito
Ilana L
IL
Sheng
Morgan
M
D000818:Animals; D001921:Brain / Q000473:pathology; D019556:COS Cells; D002522:Chlorocebus aethiops; D049229:Dendritic Spines / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D000074407:SAP90-PSD95 Associated Proteins; D025801:Ubiquitin / Q000737:chemistry; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
C120405:BERP; D009419:Nerve Tissue Proteins; D000074407:SAP90-PSD95 Associated Proteins; D025801:Ubiquitin; C033652:postsynaptic density proteins; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex