GSK3α and GSK3β Phosphorylate Arc and Regulate its Degradation

Abstract

The selective and neuronal activity-dependent degradation of synaptic proteins appears to be crucial for long-term synaptic plasticity. One such protein is activity-regulated cytoskeleton-associated protein (Arc), which regulates the synaptic content of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR), excitatory synapse strength and dendritic spine morphology. The levels of Arc protein are tightly regulated, and its removal occurs via proteasome-mediated degradation that requires prior ubiquitination. Glycogen synthase kinases α and β (GSK3α, GSKβ; collectively named GSK3α/β) are serine-threonine kinases with abundant expression in the central nervous system. Both GSK3 isozymes are tonically active under basal conditions, but their activity is regulated by intra- and extracellular factors, intimately involved in neuronal activity. Similar to Arc, GSK3α and GSK3β contribute to synaptic plasticity and the structural plasticity of dendritic spines. The present study identified Arc as a GSK3α/β substrate and showed that GSKβ promotes Arc degradation under conditions that induce de novo Arc synthesis. We also found that GSK3α/β inhibition potentiated spine head thinning that was caused by the prolonged stimulation of N-methyl-D-aspartate receptors (NMDAR). Furthermore, overexpression of Arc mutants that were resistant to GSK3β-mediated phosphorylation or ubiquitination resulted in a stronger reduction of dendritic spine width than wildtype Arc overexpression. Thus, GSK3β terminates Arc expression and limits its effect on dendritic spine morphology. Taken together, the results identify GSK3α/β-catalyzed Arc phosphorylation and degradation as a novel mechanism for controlling the duration of Arc expression and function.

Herpes Simplex Virus type 1 neuronal infection triggers disassembly of key structural components of dendritic spines

“…The inactive GSK3 enhances the inhibitory phosphorylation of CREB at Ser129, in agreement with the significant reduction of phosphorylation at Ser133 that we showed in Figure 7B. As reported before, the inhibition of GSK3β promotes Arc accumulation [53]. Altogether, the present work provides evidence that HSV-1 neuronal infection resembles many of the phenotypes induced by neurodegenerative diseases; such as spine loss and synaptic proteins down regulation, accumulation of Arc protein, and abnormal calcium levels ( Figure 9).…”

“…GSK3 activation was found to phosphorylate Arc protein and promote its degradation under conditions that induce de novo Arc synthesis. This GSK3 phosphorylation-dependent ubiquitination of residue K136, is one example of positive cross talk between post-translational modifications of Arc protein [53]. K24, K33 and K55 can also be acetylated, protecting Arc from ubiquitindependent degradation thus, stabilizing Arc halflife [54].…”

Arc Regulates Transcription of Genes for Plasticity, Excitability and Alzheimer’s Disease

“…Finally, Arc regulated genes associated with altered cognitive function, a characteristic of AD (Mmp13, Pdyn, Tac1, Bdnf, Nr4a2, Penk, Pltp and Ccl2). To date, presenilin 1 (Psen1) and glycogen synthase kinase 3 beta (Gsk3b) are the only AD mediators which have been reported to physically associate and interact with Arc [78][79][80] . Arc also interacts with endophilin 2/3 and dynamin and recruits them to early/recycling endosomes to traffic APP and beta secretase 1 (BACE1), crucial determinants of AD progression 80 .…”

Molecular determinants of Arc oligomerization and formation of virus-like capsids

“…The mechanisms that dictate Arc function at the molecular level are poorly understood. Posttranslational modification of Arc by SUMOylation (Craig et al, 2012;Nair et al, 2017) and ERKcatalyzed phosphorylation are implicated in the regulation of protein-protein interactions and subcellular localization, while Arc turnover is regulated by ubiquitination, acetylation, as well as GSK-catalyzed phosphorylation (Gozdz et al, 2017;Greer et al, 2010;Lalonde et al, 2017;Mabb et al, 2014;Wall et al, 2018). In addition, biochemical studies show that recombinant Arc protein is capable of reversible self-association (Byers et al, 2015;Myrum et al, 2015).…”