Molecular Organization and Regulation of the Mammalian Synapse by the Post-Translational Modification SUMOylation

Abstract

Neurotransmission occurs within highly specialized compartments forming the active synapse where the complex organization and dynamics of the interactions are tightly orchestrated both in time and space. Post-translational modifications (PTMs) are central to these spatiotemporal regulations to ensure an efficient synaptic transmission. SUMOylation is a dynamic PTM that modulates the interactions between proteins and consequently regulates the conformation, the distribution and the trafficking of the SUMO-target proteins. SUMOylation plays a crucial role in synapse formation and stabilization, as well as in the regulation of synaptic transmission and plasticity. In this review, we summarize the molecular consequences of this protein modification in the structural organization and function of the mammalian synapse. We also outline novel activity-dependent regulation and consequences of the SUMO process and explore how this protein modification can functionally participate in the compartmentalization of both pre- and post-synaptic sites.

Keywords: LLPS; SUMO; SUMOylation; biomolecular condensate; post-translational modification; synapse.

Figure 1

Schematic representation of the enzymatic SUMOylation/deSUMOylation cycle. The different phases of the enzymatic cascade leading to the SUMOylation of the target protein are highlighted in red. SUMO, Small Ubiquitin-like MOdifier; SAE, SUMO-activating enzyme; Ubc9, SUMO-conjugating enzyme; SENP, Sentrin protease.

Figure 2

Post-synaptic regulation of the SUMO/deSUMOylation cascade at synapses by type I mGlu1/5R. (A) A short activation of mGlu5 receptors triggers a Protein Kinase C (PKC) phosphorylation-dependent trapping of the sole SUMO-conjugating enzyme Ubc9 at post-synaptic sites, leading to an increased SUMOylation and to the modulation of neuronal excitability [19]. The sustained activation of mGlu5R then leads to a decrease in the exit rate of the deSUMOylation enzyme SENP1 from dendritic spines, resulting in the post-synaptic accumulation of SENP1 to bring SUMOylation back to initial levels [26]. (B) The post-synaptic accumulation of SENP1 upon stimulation of mGlu5R involves the downstream activation of PKC or Ca²⁺/Calmodulin-dependent protein kinase II (CaMKII). Blocking mGlu1R enhances the post-synaptic accumulation of SENP1, indicating that the SUMOylation/deSUMOylation balance is bidirectionally regulated by type I mGluRs to control the levels of synaptic SUMOylation [27].

Figure 3

Potential mechanism driving the activity-dependent protein clustering into distinct subdomains via SUMO-interacting motif (SIM)/SUMO-protein-dependent interactions.

Figure 4

Landscape of SUMOylated proteins in the compartmentalization of presynaptic sites. Consistent with the emerging presynaptic functions of SUMOylation, several presynaptic proteins are SUMO substrates: RIM1α [93], Synaptotagmin-1 [94], Synapsin-1 [95], Syntaxin-1 [96], mGluR7 [97,98] and α-synuclein [99,100]. In addition, Rab3, SV2B, Synaptophysin, VGCCs, VGLUT1, V-ATPase and Dynamin have been identified as potential SUMO targets in [72].

Figure 5

Landscape of SUMOylated proteins in the compartmentalization of post-synaptic sites. Consistent with the emerging post-synaptic functions of SUMOylation, several post-synaptic proteins are known SUMO substrates, including Kainate receptors [15,107,108] and Arc [114,115]. In addition, SynGAP, SAPAP3, PSD95, Homer1, CaMKII and Adhesion molecules like Neuroligin, N-Cadherin and β-catenin have been identified as potential SUMO targets in [72].