NAC1 regulates the recruitment of the proteasome complex into dendritic spines.
Coordinated proteolysis of synaptic proteins is required for synaptic plasticity, but a mechanism for recruiting the ubiquitin-proteasome system (UPS) into dendritic spines is not known. NAC1 is a cocaine-regulated transcriptional protein that was found to complex with proteins in the UPS, including cullins and Mov34. NAC1 and the proteasome were cotranslocated from the nucleus into dendritic spines in cortical neurons in response to proteasome inhibition or disinhibiting synaptic activity with bicuculline. Bicuculline also produced a progressive accumulation of the proteasome and NAC1 in the postsynaptic density. Recruitment of the proteasome into dendrites and postsynaptic density by bicuculline was prevented in neurons from mice harboring an NAC1 gene deletion or in neurons transfected with mutated NAC1 lacking the proteasome binding domain. These experiments show that NAC1 modulates the translocation of the UPS from the nucleus into dendritic spines, thereby suggesting a potential missing link in the recruitment of necessary proteolysis machinery for synaptic remodeling.
Shen
Haowei
H
Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Korutla
Laxminarayana
L
Champtiaux
Nicholas
N
Toda
Shigenobu
S
LaLumiere
Ryan
R
Vallone
Joseph
J
Klugmann
Matthias
M
Blendy
Julie A
JA
Mackler
Scott A
SA
Kalivas
Peter W
PW
D000818:Animals; D000831:Animals, Newborn; D001640:Bicuculline / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D044842:Cullin Proteins / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism*; D004622:Embryo, Mammalian; D018756:GABA Antagonists / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000648:ultrastructure*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D012097:Repressor Proteins; D014162:Transfection / Q000379:methods; D025801:Ubiquitin / Q000378:metabolism*
D018797:Cell Cycle Proteins; C503646:Cul3 protein, mouse; D044842:Cullin Proteins; D015853:Cysteine Proteinase Inhibitors; D018756:GABA Antagonists; D047908:Intracellular Signaling Peptides and Proteins; D007976:Leupeptins; C484605:Nacc1 protein, mouse; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D025801:Ubiquitin; C072621:Psmd7 protein, mouse; D049452:Green Fluorescent Proteins; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D001640:Bicuculline
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